TW200838508A - Chemical compounds - Google Patents
Chemical compounds Download PDFInfo
- Publication number
- TW200838508A TW200838508A TW097103388A TW97103388A TW200838508A TW 200838508 A TW200838508 A TW 200838508A TW 097103388 A TW097103388 A TW 097103388A TW 97103388 A TW97103388 A TW 97103388A TW 200838508 A TW200838508 A TW 200838508A
- Authority
- TW
- Taiwan
- Prior art keywords
- trans
- amino
- methyl
- azaspiro
- oxa
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Addiction (AREA)
- Psychiatry (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Reproductive Health (AREA)
- Immunology (AREA)
- Gynecology & Obstetrics (AREA)
- Ophthalmology & Optometry (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Pregnancy & Childbirth (AREA)
- Emergency Medicine (AREA)
- Anesthesiology (AREA)
- Child & Adolescent Psychology (AREA)
- Vascular Medicine (AREA)
- Pulmonology (AREA)
Abstract
Description
200838508 九、發明說明: 【發明所屬之技術領域】 本發明關於新穎的化合物、彼等之製備法、被使用於 這些製法中之中間物、含彼等之藥學的組成物及彼等用於 5 作為NPY Y5受體拮抗劑類以及作為供治療及/或預防飲 食方面疾病’例如狂吃症(binge eating disorder)之藥劑的 療法上之用途。 •【先前技術】 10 神經胜肽Y(Neuropeptide Y,後面稱之為NPY),係一 種由36個胺基酸組成之胜狀,最先在1982年由Tatemoto 等人從豬腦分離得到[Nature,296: 659 (1982)],NPY廣佈 於中柩及周圍神經系統且扮演多種的角色而為神經系統 中最豐富的胜肽;NPY在中樞神經系統中作用為一種促食 15 的物質(orexigenic substance)且經由各種激素的分泌作用 或神經系統的作用之媒介而明顯地促進脂肪蓄積,已知, _ 基於這些作用,連續的經腦室内投與NPY,會誘導肥胖及 胰島素抗性(International Journal of Obesity,vol. 19: 517 (1995); Endocrinology, vol· 133: 1753(1993));也已知, 20 NPY具有相關於與像是憂鬱、焦慮、人格分裂、疼痛、癡 呆等疾病之重要影響(Drugs,vol· 52, 371(1996),此外,在 周圍神經中,ΝΡΥ與正腎上腺素(norepinephrine) —起存在 於交感神經末端且參與交感神經系統之強直性;已知,在 周圍神經施用NPY會造成血管收縮並提高其他血管收縮 200838508 物質(例如’正腎上腺素)之活性(British Journal of Pharmacology,vol.95: 419 (1988));也有報導認為,由於交 感神經的刺激結果,NPY可能參與心臟肥大之發展 (Proceeding National Academic Science USA,Vol· 97, 5 1595(2000)) 〇 結合NPY及作為配體之相關的多肽類之内源性受體 蛋白質已被鑑定及區別,且許多這類蛋白質已被選殖及表 現,現今,根據已知的結合類型、藥理學及/或組成,已 ® 有六種不同的受體子型[Yl、Y2、Y3、Y4〇PP)、Y5、Y6] ^10 被辨認。 Υ5子型的分離、鑑別及報告,最近被發表於US Patent 5,602,024 (WO 96/16542);被NPY Y5受體媒介的影響包 括飲食刺激及脂肪的蓄積(Nature,vol. 382,168(1996)); American Journal of Physiology,vol· 277, R1428 (1999)), 15 也有報導指出,NPY Y5受體也媒介一些CNS影響,例如, 發作及癲癇,或是疼痛及嗎啡戒斷症狀(Natural Medicine, • vol· 3,761(1997); Proceeding Academic Science USA,vol· 96,13518(1999); The Journal of Pharmacology and Experimental Therapetics,vol· 284,633(1998));在周圍系 2〇 統中,NPY Y5受體被報導參與於由NPY造成之尿多症及 低 i 糖影響(British Journal of Pharmacology,vol. 120, 1335(1998); Endocrinology,vol· 139,3018(1998)); NPY 也 被報導,在交感神經的強化結果下增加心肌肥大 (Proceeding National Academic Science USA,Vol· 97, 200838508 1595(2000)) 〇 ΝΡΥ的影響藉由結合至中樞或周圍神經系統中之 ΝΡΎ受體而出現,於是,ΝΡΥ的作用可藉由阻斷結合至 ΝΡΥ受體而被防止,用於拮抗ΝΡΥ結合至ΝΡΥ受體的物 5 質可能有用於供預防或治療各種相關於ΝΡΥ的疾病,例 如,心血管疾病類(例如,高血壓、腎病、心臟病、血管 痙攣)、中樞神經系統疾病類(例如,飢餓、狂吃、憂鬱、 焦慮、發作、癲癇、癡呆、痛苦、酗酒、藥物戒斷)、代 ® 謝性疾病類(例如,肥胖、糖尿病、激素異常)、性及生殖 -10 功能異常、胃-腸蠕動性疾病、呼吸異常、炎症或青光眼 等等(Trends in Pharmacological Sciences,15: 153(1994); Life Science,· 55,551(1994); Drugs,vol. 52,371(1996); The Journal of Allergy and Immunology,vol· 101, S345(1998); Nature,vol· 396,366(1998); The Journal of 15 Pharmacology and Experimental Therapeutics, vol.284? 633(1998); Trends in Pharmacological Science,vol. 20, Φ 104(1999); Proceeding National Academic Science USA? vol. 97,1595(2000)) 〇 20 【發明内容】 本發明的目的係提供具式⑴的化合物或其一種藥學 上可接受的鹽或溶劑化物: 200838508200838508 IX. OBJECTS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds, their preparation, intermediates used in these processes, compositions containing the same, and their use in 5 It is used as a therapeutic agent for NPY Y5 receptor antagonists and as a medicament for the treatment and/or prevention of dietary diseases such as binge eating disorders. • [Prior Art] 10 Neuropeptide Y (hereinafter referred to as NPY), a victory consisting of 36 amino acids, first isolated from pig brain by Tatemoto et al. in 1982 [Nature , 296: 659 (1982)], NPY is widely distributed in the middle and peripheral nervous system and plays a variety of roles and is the most abundant peptide in the nervous system; NPY acts as a substance that promotes 15 in the central nervous system ( Orexigenic substance) and significantly promotes fat accumulation via the secretion of various hormones or the action of the nervous system. It is known that _ based on these effects, continuous intraventricular administration of NPY induces obesity and insulin resistance (International Journal of Obesity, vol. 19: 517 (1995); Endocrinology, vol. 133: 1753 (1993)); also known, 20 NPY is associated with diseases such as depression, anxiety, personality division, pain, dementia, etc. Important effects (Drugs, vol. 52, 371 (1996), in addition, in the peripheral nerves, sputum and norepinephrine are present at the sympathetic end and participate in the tonicity of the sympathetic nervous system; Peripheral nerve administration of NPY causes vasoconstriction and increases the activity of other vasoconstrictors 200838508 (eg, 'positive adrenaline) (British Journal of Pharmacology, vol. 95: 419 (1988)); it is also reported that sympathetic stimulation results NPY may be involved in the development of cardiac hypertrophy (Proceeding National Academic Science USA, Vol. 97, 5 1595 (2000)) 内 Endogenous receptor proteins that bind NPY and related polypeptides as ligands have been identified and distinguished. And many of these proteins have been cloned and expressed. Today, there are six different receptor subtypes [Yl, Y2, Y3, Y4〇PP) based on known binding types, pharmacology and/or composition. , Y5, Y6] ^10 was identified. Separation, identification and reporting of the Υ5 subtype has recently been published in US Patent 5,602,024 (WO 96/16542); effects by NPY Y5 receptor media include dietary stimuli and accumulation of fat (Nature, vol. 382, 168 (1996) American Journal of Physiology, vol. 277, R1428 (1999)), 15 It has also been reported that NPY Y5 receptors also mediate some CNS effects, such as seizures and epilepsy, or pain and morphine withdrawal symptoms (Natural Medicine, • vol. 3, 761 (1997); Proceeding Academic Science USA, vol. 96, 13518 (1999); The Journal of Pharmacology and Experimental Therapetics, vol. 284, 633 (1998)); The NPY Y5 receptor has been reported to be involved in urinary dysfunction and low i-glycan effects caused by NPY (British Journal of Pharmacology, vol. 120, 1335 (1998); Endocrinology, vol. 139, 3018 (1998)); NPY has also been Reports that increased cardiac hypertrophy under sympathetic enhancement results (Proceeding National Academic Science USA, Vol. 97, 200838508 1595 (2000)) The effects of sputum by binding to sputum receptors in the central or peripheral nervous system Thus, the action of sputum can be prevented by blocking binding to the sputum receptor, and the substance used to antagonize sputum binding to the sputum receptor may be used for the prevention or treatment of various diseases associated with sputum, for example, heart Vascular diseases (eg, hypertension, kidney disease, heart disease, vasospasm), central nervous system diseases (eg, hunger, madness, depression, anxiety, seizures, epilepsy, dementia, pain, alcoholism, drug withdrawal), Generation® (eg obesity, diabetes, hormonal abnormalities), sexual and reproductive-10 dysfunction, gastric-intestinal motility, respiratory abnormalities, inflammation or glaucoma, etc. (Trends in Pharmacological Sciences, 15: 153 ( 1994); Life Science, 55, 551 (1994); Drugs, vol. 52, 371 (1996); The Journal of Allergy and Immunology, vol. 101, S345 (1998); Nature, vol. 396, 366 (1998) The Journal of 15 Pharmacology and Experimental Therapeutics, vol. 284? 633 (1998); Trends in Pharmacological Science, vol. 20, Φ 104 (1999); Proceeding National Academic Science USA? vol. 97,1595(2000)) 〇 20 SUMMARY OF THE INVENTION The object of the present invention is to provide a compound of the formula (1) or a pharmaceutically acceptable salt or solvate thereof: 200838508
其中 R 為一種芳基或雜芳基,其可經一或多個的下述基取代: _ 鹵素、C1-C4烷基、C1-C4烷氧基、C1-C4鹵基烷基、 5 C1-C4鹵基烷氧基、氰基; Ζι 為Η、C1-C4烷基或F ; Ζ 為 CH2、CH(C1-C4 烷基)、€:(01-04烷基)2或一種鍵 結; A 為一種5成員的雜芳基,其可經一或多個的下述基取 ίο 代:鹵素、C1-C4烷基、C1-C4烷氧基、C1-C4鹵基 烷基、C1-C4鹵基烷氧基、氰基; • B 為氫或為一種5-6成員的雜芳基,或苯基,其可經一 或多個的下述基取代:鹵素、C1-C4烷基、C1-C4烷 氧基、C1-C4鹵基烷基、C1-C4鹵基烷氧基、氰基;A 15 及B可經由任一原子被連結。 本發明的化合物可以呈現為一種藥學上可被接受的 鹽型式及/或被投與,適當的鹽類之回顧,可參考:Bergeet al,J· Pharm· Sci·,1977, 66, 1-19。 -ίο- 200838508 典型地,藥學上可接受的鹽可輕易地使用一種想要的 酸或鹼來製備,此鹽可自溶液中沈澱並藉由過濾收集或藉 由蒸發除去溶劑而被回收。 適當的藥學上可接受的加成鹽類為形成自可形成無 5 毒性的鹽類之酸類,實例為:鹽酸鹽、氫溴酸鹽、氫碘酸 鹽、硫酸鹽、硫酸氫鹽、硝酸鹽、磷酸鹽、磷酸氫鹽、乙 酸鹽、順丁烯二酸鹽、蘋果酸鹽、反丁烯二酸鹽、乳酸鹽、 酒石酸鹽、檸檬酸鹽、曱酸鹽、葡萄糖酸鹽、琥珀酸鹽、 ® 丙酮酸鹽、草酸鹽、草酸乙酸鹽、三氟乙酸鹽、蔗糖酸鹽、 40 苯甲酸鹽、曱石黃酸鹽、乙石黃酸鹽、苯石黃酸鹽、對-曱苯石黃 酸鹽、及羥基乙磺酸鹽。 藥學上可接受的鹼鹽類包括銨鹽類、鹼金屬鹽類(例 如,納與鉀之鹽類)、驗土金屬鹽類(例如,妈與鎮之鹽類)、 以及與有機鹼類形成之鹽類,包括與一級、二級、三級胺 15 類(例如,異丙基胺、二乙基胺、乙醇胺、三曱基胺、二 環己基胺及N-甲基葡糖胺)形成之鹽類。 • 藥學上可接受的鹽類也可製自其他的鹽類,包括使用 傳統方法製得之式(I)化合物之其他藥學上可接受的鹽類。 熟悉有機化學的行家知道,許多的有機化合物可與其 20 進行反應的溶劑或從其中沈澱或從其中析出結晶之溶劑 形成複合物,此複合物即為一般所知之「溶劑化物」,例 如,與水形成之複合物即為所知之一種「水合物」,本發 明的化合物之溶劑化物被涵蓋於本發明的範圍之中。 此外,本發明内文中也包含前劑(prodrug)。 -11- 200838508Wherein R is an aryl or heteroaryl group which may be substituted by one or more of the following groups: _ halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, 5 C1 -C4 haloalkoxy, cyano; Ζι is Η, C1-C4 alkyl or F; Ζ is CH2, CH(C1-C4 alkyl), €: (01-04 alkyl) 2 or a bond A is a 5-membered heteroaryl group which may be substituted by one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1 -C4 haloalkoxy, cyano; B is hydrogen or a 5-6 membered heteroaryl, or phenyl which may be substituted by one or more of the following: halogen, C1-C4 alkane a group, a C1-C4 alkoxy group, a C1-C4 haloalkyl group, a C1-C4 haloalkoxy group, a cyano group; A15 and B may be bonded via any atom. The compounds of the invention may be presented as a pharmaceutically acceptable salt form and/or administered, and a review of suitable salts can be found in: Bergeve al, J. Pharm. Sci., 1977, 66, 1-19 . - ίο- 200838508 Typically, a pharmaceutically acceptable salt can be readily prepared using a desired acid or base which can be precipitated from solution and recovered by filtration or by solvent removal by evaporation. Suitable pharmaceutically acceptable addition salts are those which form salts which form no toxicities, examples being: hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitric acid Salt, phosphate, hydrogen phosphate, acetate, maleate, malate, fumarate, lactate, tartrate, citrate, citrate, gluconate, succinic acid Salt, ® pyruvate, oxalate, oxalic acid acetate, trifluoroacetate, sucrose, 40 benzoate, sulphate, ethinger, behenate, p- Panthonite, and isethionate. The pharmaceutically acceptable alkali salts include ammonium salts, alkali metal salts (for example, salts of sodium and potassium), soil metal salts (for example, salts of Ma and town), and organic bases. Salts, including with primary, secondary, tertiary amines 15 (eg, isopropylamine, diethylamine, ethanolamine, tridecylamine, dicyclohexylamine, and N-methylglucamine) Salt. • Pharmaceutically acceptable salts can also be prepared from other salts, including other pharmaceutically acceptable salts of the compounds of formula (I) which are prepared by conventional methods. Those skilled in the art of organic chemistry know that many organic compounds can form a complex with a solvent which reacts with 20 or a solvent which precipitates or precipitates therefrom, and the complex is a generally known "solvate", for example, The complex formed by water is a known "hydrate", and solvates of the compounds of the present invention are encompassed within the scope of the present invention. In addition, prodrugs are also included in the text of the present invention. -11- 200838508
-10 15 20 在此,所稱之「前劑」意指一種化合物,其在體内, 例如,藉由在血液中之水解,被轉變成其具有醫藥效果的 活性型式者,藥學上可接受的前劑類被描述於:T· Higuchi and V· Stella,Prodrugs as Novel Delivery Systems,Vol· 14 of the A.C.S· Symposium Series,Edward Β· Roche,ed·, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press,1987,以 及於 D· Fleisher, S· Ramon and Η· Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugsn5 Advanced Drug Delivery Reviews (1996) 19(2) ’其各被併入於此做為茶考。 所謂的前劑也包含,當這樣的前劑被投與給患者時, 在生體内可釋放出具式(I)結構的化合物之任何被共價結 合著的載劑;前劑通常是藉由修飾官能基使其能利用例行 的操作或在生體内被斷裂而產生原化合物之修飾方式被 製備者,前劑包括,例如,其中胺基被束缚於任何基團上 的本發明的化合物,當投與給患者時,可斷開而形成胺基 者,於是,前劑之代表性實例包括(但非限於):具式⑴結 構的化合物之胺官能基之乙酸酯、甲酸酯及苯曱酸酯衍生 物。 立體異構物方面,式(I)的化合物可能具有一或多個不 對稱的碳原子,且可能呈現為外消旋異構物、外消旋異構 物混合物及個別的鏡像物或非鏡像物,所有這樣的異構物 型式均被涵蓋於本發明的範圍内,包括其混合物。 -12- 200838508 當有需要一種式⑴化合物的特定之鏡像物時,其取得 可利用,例如,解析式(I)化合物之一種相關的鏡像物混合 物而得,係使用傳統方法,例如H.RL.C.,使用一種適當 的對掌支撐物或藉由分劃結晶法,將相關的外消旋異構物 5 與一種適當的光學上活性酸或鹼進行適當的反應所得之 非鏡像物鹽類分開;或是,一種特定之鏡像物也可由相關 的光學上純態中間物來製備。 非鏡像物、或順式及反式異構物或同侧及反侧異構物 ® 的分離可藉由傳統技術,例如,分劃結晶法、層析法或 -10 H.RL.C·法,分離一種立體異構性混合物而達成。 此外,式(I)化合物之一些晶體型式可呈現多形體型式 存在,其被涵蓋於本發明的範圍中。 所謂的C1-C4烷基,係指一種基或基之一部分,為含 有自1至4個碳原子之線型或支鏈型烷基;這類基之實例 15 包括,曱基、乙基、丙基、異丙基、正丁基、異丁基、第 三-丁基。 • 所謂的鹵素係指氟、氯、溴或碘原子。 所謂之鹵基C1-C4烷基係指具有1至4個碳原子且其 中至少有一個氫原子被鹵素取代之一種烧基,例如,三氟 20 曱基等等。 所謂的C1-C4烷氧基可以是一種線型或支鏈型之烷 氧基,例如,曱氧基、乙氧基、丙氧基、丙-2_氧基、丁氧 基、丁 -2-乳基或曱基丙-2-氧基、等等。 所謂的鹵基C1-C4烷氧基係指經至少一個鹵素(較佳 -13- (B ) 200838508 地為氟)取代之如前面已定義之C1-C4烷氧基,例如, OCHF2、或 OCF3。 所謂之芳基係指一種具有6至12個成員之一種芳族 碳環,代表性之芳基包括(但非限於):苯基、聯苯基或萘 5 基。 所謂之雜芳基係指一種具有5至10個成員且具有至 少一個挑選自氮、氧及硫的雜原子,且含有至少一個碳原 子之芳族的雜環,包括單-及雙-環系統兩者。 ® 代表性雜芳基類包括(但非限於)··呋喃基、苯并呋喃 10 基、硫苯基、苯弁硫苯基、吼洛基、叫卜朵基、異叫丨ϋ朵基、 氮雜17引嗓基、吼11定基、嗓琳基、異啥σ林基、哇基、異4 嗤基、苯并今嗤基、吼嗤基、味嗤基、苯并味唾基、嗟嗤 基、苯并嗟嗤基、異嗟嗤基、噠榜基、嘴咬基、吼喷基、 三口井基、嗜π林基、酜U井基、三嗤基、四嗤基、喧嗤淋基、 15 苯并二噚茂基、苯并嘆二嗤基、苯并呤二唆基、咪嗤并 [l,2-a]吼哜基、異噻唑基、噻二唑基、[1,2,4]噻唑[1,5-9] 馨 吼σ定基。 代表性之5成員的雜芳基類包括(但非限於):呋喃 基、硫苯基、吼咯基、畤唑基、異畤唑基、吼唑基、咪唑 20 基、售嗤基、異嗟峻基、三哇基、四嗤基、異嗟哇基、嗟 二口圭基。 代表性之5-6成員的雜芳基類包括(但非限於):呋喃 基、硫苯基、吡咯基、吲哚基、吡啶基、啐唑基、異畤唑 基、吼唾基、咪嗤基、喧嗤基、異嘆嗤基、噠喷基、鳴咬 -14- 200838508 基、吼呀基、三啡基、三嗤基、四嗤基、異嗔嗤基、嗟二 σ坐基。 就立體異構物而言,式(I)的化合物-10 15 20 Herein, the term "prodrug" means a compound which is pharmaceutically acceptable in vivo, for example, by being hydrolyzed in blood, into an active form having a medicinal effect. The prodrug class is described in: T· Higuchi and V· Stella, Prodrugs as Novel Delivery Systems, Vol· 14 of the ACS· Symposium Series, Edward Β· Roche, ed·, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and Η Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugsn5 Advanced Drug Delivery Reviews (1996) 19(2) 'each of which is incorporated This is a tea test. The so-called prodrug also comprises, when such a prodrug is administered to a patient, any covalently bound carrier of the compound of formula (I) can be released in the body; the prodrug is usually The modification of the functional group allows it to be prepared by a conventional operation or a modification in which the original compound is cleaved in a living body, and the prodrug includes, for example, a compound of the present invention in which an amine group is bound to any group. When administered to a patient, it can be cleaved to form an amine group. Thus, representative examples of the prodrug include, but are not limited to, acetate, formate, of an amine functional group of a compound of the formula (1). And benzoate derivatives. In terms of stereoisomers, the compound of formula (I) may have one or more asymmetric carbon atoms and may be present as a racemic isomer, a mixture of racemic isomers and individual mirror images or non-mirrored. All such isomeric forms are encompassed within the scope of the invention, including mixtures thereof. -12- 200838508 When there is a need for a particular mirror image of a compound of formula (1), it is available, for example, to resolve a related mixture of mirror compounds of a compound of formula (I) using conventional methods such as H.RL. .C., a non-image-image salt obtained by suitably reacting the relevant racemic isomer 5 with a suitable optically active acid or base using a suitable palm support or by fractional crystallization. Classes are separated; alternatively, a particular mirror image can also be prepared from related optically pure intermediates. Separation of non-image, or cis and trans isomers or ipsilateral and dimeric isomers can be accomplished by conventional techniques such as, for example, fractional crystallization, chromatography or -10 H.RL.C. , achieved by isolating a mixture of stereoisomers. Furthermore, some of the crystal forms of the compounds of formula (I) may exist in the form of polymorphs, which are encompassed within the scope of the invention. By C1-C4 alkyl, a radical or a moiety of a radical is a linear or branched alkyl radical having from 1 to 4 carbon atoms; and examples 15 of such radicals include fluorenyl, ethyl, and propyl. Base, isopropyl, n-butyl, isobutyl, tert-butyl. • Halogen means a fluorine, chlorine, bromine or iodine atom. The halo-based C1-C4 alkyl group means an alkyl group having 1 to 4 carbon atoms and at least one of the hydrogen atoms is substituted by a halogen, for example, a trifluoro 20 fluorenyl group or the like. The so-called C1-C4 alkoxy group may be a linear or branched alkoxy group, for example, a decyloxy group, an ethoxy group, a propoxy group, a prop-2-oxy group, a butoxy group, a but-2- Milk-based or mercaptoprop-2-oxy, and the like. The so-called halo-C1-C4 alkoxy refers to a C1-C4 alkoxy group as defined above substituted with at least one halogen (preferably -13-(B) 200838508), for example, OCHF2, or OCF3. . By aryl is meant an aromatic carbocyclic ring having from 6 to 12 members, and representative aryl groups include, but are not limited to, phenyl, biphenyl or naphthalene. By heteroaryl is meant a heterocyclic ring having from 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least one carbon atom, including mono- and bi-ring systems. Both. ® Representative heteroaryls include, but are not limited to, furyl, benzofuran 10, thiophenyl, phenyl sulfonyl phenyl, fluorenyl, bromo, fluorenyl, Aza 17 fluorenyl, hydrazine 11 decyl, fluorenyl, isoindole sylylene, wow, iso 4 fluorenyl, benzoxenyl, fluorenyl, miso, benzopyran, hydrazine Sulfhydryl, benzofluorenyl, isodecyl, ruthenium, mouth bite, hydrazine, three wells, π-lin, 酜U well, triterpene, tetradecyl, fluorene Lysyl, 15 benzodioxanyl, benzoindole, benzofluorenyl, indolo[l,2-a]decyl, isothiazolyl, thiadiazolyl, [1, 2,4]thiazole [1,5-9] 吼 吼 σ base. Representative 5-membered heteroaryl groups include, but are not limited to, furyl, thiophenyl, decyl, oxazolyl, isoxazolyl, oxazolyl, imidazolyl 20, sold in, and Yan Junji, Sanwaji, Sijiji, Yiweiwaji, and Qiji. Representative 5-6 member heteroaryls include, but are not limited to, furyl, thiophenyl, pyrrolyl, indolyl, pyridyl, oxazolyl, isoxazolyl, indolyl, imi Sulfhydryl, sulfhydryl, singly sulphonyl, hydrazine, spurt-14- 200838508 ketone, euphorbia, trimorphine, triterpene, tetradecyl, isodecyl, ruthenium . In the case of stereoisomers, the compounds of formula (I)
Ζ-Ν^Β • Η .5 可有兩種立體異構物存在,分別以式(la)及(lb)代表。Ζ-Ν^Β • Η .5 There are two stereoisomers present, represented by formulas (la) and (lb), respectively.
一具體實施例中,被提供的式(la)化合物之立體化學 1〇 為「順式」,除了當冗1為F,其立體化學為「反式」;本發 明的另一具體實施例中,提供式(lb)的化合物,其中立體 化學為「反式」,除了當Z】為F,其立體化學為「順式」; 「反式」立體化學係根據Kahn-Prelog-Ingold分類法,附 接至環己烷環之最優先的基團為位於環己烷環之相對邊 而定;「反式」立體化學也可被標示為「反式組態」或「反 -15- 15 200838508 侧(anti)」;在式⑴的情況,標示符號(5r,8 r)也可被用於描 述「反式」立體化學。 就某方面,本發明提供式(I)、(la)及(lb)的化合物,其 中: 5In one embodiment, the stereochemistry of the compound of formula (la) is provided as "cis", except that when the redundancy 1 is F, the stereochemistry is "trans"; in another embodiment of the invention Providing a compound of the formula (lb) wherein the stereochemistry is "trans", except that when Z is F, the stereochemistry is "cis"; the "trans" stereochemistry is according to the Kahn-Prelog-Ingold classification, The most preferred group attached to the cyclohexane ring is located on the opposite side of the cyclohexane ring; the "trans" stereochemistry can also be labeled as "trans configuration" or "anti-15-15 200838508 "anti"; in the case of equation (1), the designation (5r, 8r) can also be used to describe "trans" stereochemistry. In one aspect, the invention provides compounds of formula (I), (la), and (lb), wherein: 5
40 1540 15
20 R 為苯基或呋喃基、苯并呋喃基、硫苯基、苯并硫苯基、 °比口各基、吲哚基、異吲哚基、氮雜吲哚基、°比唆基、 σ奎琳基、異哇ϋ林基、今嗤基、異4哇基、苯并4嗤基、 吼σ坐基、味哇基、苯并味嗤基、σ塞唾基、苯并σ塞嗤基、 異嗟哇基、噠呼基、嘴咬基、σ比喷基、三啡基、噌琳 基、酜ϋ井基、三ΰ坐基、四嗤基、啥嗤琳基、苯并二口号 茂基、苯并噻二唑基、苯并噚二唑基、咪唑并[l,2-a] 吡畊基、異噻唑基、噻二唑基、[1,2,4]噻唑[1,5-9]吡 啶基,其可經一或多個的下述基取代:鹵素、C1-C4 烷基、C1-C4烷氧基、C1-C4鹵基烷基、C1-C4鹵基 烷氧基、氰基; A 為挑選自包括下述基:吱喃基、硫苯基、σ比洛基、吟 σ坐基、異今唾基、σ比唾基、味嗤基、σ塞嗤基、異嗟唾 基、三TJ坐基、四唾基、異σ塞唾基、ϋ塞二σ坐基,其可經 一或多個的下述基取代:鹵素、C1-C4烷基、C1-C4 烷氧基、C1-C4鹵基烷基、C1-C4鹵基烷氧基、氰基; Β 為苯基或吼啶,其可經一或多個的下述基取代:鹵 素、C1-C4烷基、C1-C4烷氧基、C1-C4鹵基烷基、 C1-C4鹵基烷氧基、氰基。 本發明之示範性化合物包括: -16- 200838508 (順式)3-苯基_8_({[4-(2-吼啶基)_ι,3_噻唑:基]胺基}甲 基)·1-氧雜冬氮雜螺[4·5]_癸烷-2-酮; (反式)-3-苯基-8-({[4_(2_σ比啶基)4,3-噻唑_2_基]胺基}甲 基)-1-氧雜-3-氮雜螺_[4·5]癸燒-2-酮; 5 (皮式)·8_({[4"·(6-曱基比啶基)-1,3-嗟唑_2-基]胺基}甲 基)-3-苯基-1-氧雜—3-氮雜螺[4.5]癸烷-2-酮; (反式)-8-({[4-(6-甲基-2-吼啶基)-i,3-噻唑-2-基]胺基}甲 基)-3-本基-1-氧雜·3_氮雜螺[4.5]癸烧_2-酉同; •(反式”-“㈣3·曱基比啶基Μ,3-噻嗤_2_基]胺基}甲 4〇 基)-3_苯基-1·氧雜-3-氮雜螺[4·5]癸烷-2_酮; (反式)=-({[4-(3-甲基_2_吡啶基噻唑_2_基]胺基}曱 基)-3-苯基-1-氧雜-3-氮雜螺[4.5]癸烷酮; (反式)-3-(2-吼啶基)-8_({[4_(2·吡啶基)_u_噻唑_2_基]胺基} 甲基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮; 15 (反式)—3_(4_氟苯基)·8-({[4-(2-吼啶基)-1,3-噻唑-2_基]胺基} 甲基)-1-氧雜-3-氮雜螺[4·5]癸烷-2-酮; •(反式)各(2-氟苯基){({[4-(2』比口定基)],3-π塞冬2-基]胺基} 曱基)-1-氧雜-3-氮雜螺[4·5]癸烷-2-酮; (順式)-3 =吡啶基Η_({[4♦吡啶基”心塞唾冬基]胺基} 2〇 甲基戶1·氧雜_3-氮雜螺-[4.5]癸烷-2-酮; (反式)-3:0-吼唆基)1({[4_(2_吼咬基)H售唾_2·基]胺基} 甲基)-1-氧雜-3-氮雜螺[4·5]癸烷_2_酮; (反式)冬({[4-(3-氟| π比咬基)·!,3_ D塞唾I基]胺基}甲 基)_3_(3』比啶基)小氧雜_3_氮雜螺[4.5]癸烷-2-g同; -17- 200838508 (反式)-3-(2-甲基-3_吡啶基)_8·({[4_(2_吡啶基>1,3-噻唑_2_ 基]胺基}甲基)-l-氧雜_3-氮雜螺[4·5]癸烷-2-酮; (反式)-8-({[4-(2-吡啶基)-ΐ,3-噻唑基]胺基}甲基)_3-(5-唯咬基)-1 •氧雜-3-氮雜螺[4 · 5 ]癸烧-2 -酮; 5 (順式甲基_3_(2』比啶基)冬({[4-(2』比啶基)_1,3_嗟唑一2-基]胺基}甲基)-1-氧雜_3_氮雜螺[4.5]癸烷_2_酮; (反式)-8•甲基-3-(2-吡啶基)-8_({[4_(2_吡啶基)4,3-噻唑_2_ φ 基]胺基}甲基Ρ1-氧雜-3-氮雜螺[4·5]癸烷-2-酮; (反式)-Η6_甲基〜比啶基)_8_({[4_(2_吡啶基嘆唑-2_ 10 基]胺基丨曱基卜1·氧雜冬氮雜螺[4·5]癸烧_2_酮; (反式)_3_(6-氟〜比咬基)冬({[4〇比啶基)_u_嘆唑冬基] 胺基}曱基)-1-氧雜-3-氮雜螺[4·5]癸烧-2-酮; (反式)各(2♦定基)_8_(1,_(2_σ比咬基)_u令坐1基]胺 基}乙基)-1-氧雜-3-氮雜螺[4·5]癸烷_2_酮; 15 (反式)冬({[5_氟吡啶基)_1,3_噻唑-2-基]胺基}甲 基)-3-(2』比咬基)小氧雜士氮雜螺[4·5]癸m同; (反式)1({[1_(2_氟苯基)_1Hn_3_基]胺基}曱基)_3普 氟-3-吡^疋基)-1-氧雜-3-氮雜螺[4·5]癸烷_2_酮; (反式)各({[1-(2-氟苯基)_1Η十坐冬基]胺基}曱基)冬π 20 噠畊基卜1氧雜·3_氮雜螺[4·5]癸烷-2_酮·20 R is phenyl or furanyl, benzofuranyl, thiophenyl, benzothiophenyl, ° specific, fluorenyl, isodecyl, azaindolyl, thiol, σ 奎 琳 基 异, 异 ϋ ϋ 、, 嗤 嗤 、, 4 哇 、 、 苯 苯 苯 苯 苯 苯 苯 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 味 味 味 坐 坐 σ Sulfhydryl, isoindolyl, oxime, mouth bite, σ ratio spray, trimorphine, 噌琳基, 酜ϋ井基, 三ΰ坐基, 四嗤基, 啥嗤琳基, benzo Di-n-mercapto, benzothiadiazolyl, benzoxadiazolyl, imidazo[l,2-a]pyrylene, isothiazolyl, thiadiazolyl, [1,2,4]thiazole [1 , 5-9]pyridyl, which may be substituted by one or more of the following: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkyl Alkoxy, cyano; A is selected from the following groups: fluorenyl, thiophenyl, σ-l- yl, 吟σ, sir, sigma, sigma, sigma, sigma a base, an isoindolyl group, a tri-TJ-based group, a tetra-s-s-yl group, an iso-sigma-saltyl group, a stagnation-sigma-s-syl group, which may be substituted by one or more of the following groups Halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano; Β phenyl or acridine, which may be passed through one or more Substituted for the following: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano. Exemplary compounds of the invention include: -16- 200838508 (cis) 3-phenyl-8-({[4-(2-acridinyl)), 3-thiazole:yl]amino}methyl)·1 -oxasoaspine[4.5]-nonane-2-one; (trans)-3-phenyl-8-({[4_(2_σ-pyridyl)-4,3-thiazole_2_ Amino]methyl}methyl)-1-oxa-3-azaspiro-[4·5]indole-2-one; 5 (leather)·8_({[4"·(6-fluorenyl) Pyridyl)-1,3-oxazol-2-yl]amino}methyl)-3-phenyl-1-oxa-3-azaspiro[4.5]decane-2-one; -8-({[4-(6-methyl-2-acridinyl)-i,3-thiazol-2-yl]amino}methyl)-3-benz-1-one 3_Azaspiro[4.5]癸烧_2-酉同; •(trans)-“(tetra)3·曱pyridinylpurine, 3-thiazol-2-yl]amino}methyl-4-indenyl)- 3_phenyl-1·oxa-3-azaspiro[4·5]nonane-2-one; (trans)=-({[4-(3-methyl-2-pyridylthiazole) 2-(amino)amino}indolyl-3-phenyl-1-oxa-3-azaspiro[4.5]decane ketone; (trans)-3-(2-acridinyl)-8_( {[4_(2·pyridyl)_u_thiazole-2-yl]amino}methyl)-1-oxa-3-azaspiro[4.5]decane-2-one; 15 (trans)— 3-(4-fluorophenyl)·8-({[4-(2-acridinyl)-1,3-thiazole-2-yl) ]amino}methyl)-1-oxa-3-azaspiro[4·5]nonan-2-one; • (trans) each (2-fluorophenyl){({[4-( 2"Butylation of the base]], 3-π塞冬二基基基} 曱))-1-oxa-3-azaspiro[4·5]nonan-2-one; (cis) -3 = pyridyl hydrazine _ ({[4 ♦ pyridyl" cisplatinyl] amine group 2 〇 methyl ketone 1 oxa _ 3- azaspiro-[4.5] decane-2-one; Trans)-3:0-fluorenyl)1({[4_(2_吼))H sold sal _2·yl]amino}methyl)-1-oxa-3-azaspiro[ 4·5] decane-2 ketone; (trans) winter ({[4-(3-fluoro| π ratio)), 3_D-saltyl]amino}methyl)_3_(3比 啶 基 ) 小 ) ) 3 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 {[4_(2_pyridyl) 1,3-1,3-thiazol-2-yl]amino}methyl)-l-oxa-3-azinospiro[4·5]nonan-2-one; -8-({[4-(2-pyridyl)-indole, 3-thiazolyl]amino}methyl)_3-(5-only dimethyl)-1 oxa-3-aza snail [4 · 5 ] 癸 2 - ketone; 5 (cis methyl _3_(2 』pyridyl) winter ({[4-(2" pyridine)), 3 oxazol-2-yl Amino}methyl)-1-oxa-3-azaspiro[4.5]decane-2-ketone; (trans)-8 Methyl-3-(2-pyridyl)-8_({[4_(2_pyridyl)4,3-thiazole_2_ φ)]amino}methyl Ρ 1-oxa-3-azaspiro[4 · 5] decane-2-one; (trans)-Η6_methyl~pyridyl)_8_({[4_(2_pyridyl- oxazole-2-10 base]-aminopurinyl) Heterophyllum aza snail [4·5] sputum _2 ketone; (trans) _3_(6-fluoro~bybite) winter ({[4 〇 pyridine)) _u_ azole azole base] }曱))-1-oxa-3-azaspiro[4·5]oxadol-2-one; (trans) each (2♦ fixed) _8_(1,_(2_σ ratio bite)_u order Sodium 1]amino}ethyl)-1-oxa-3-azaspiro[4·5]nonane-2-one; 15 (trans) winter ({[5-fluoropyridyl)_1, 3_thiazol-2-yl]amino}methyl)-3-(2) than bite base) Oxygen aza nitrogen snail [4·5] 癸m with; (trans) 1 ({[1_(( 2-fluorophenyl)_1Hn_3_yl]amino}indenyl)_3Pfluran-3-pyridinyl)-1-oxa-3-azaspiro[4·5]nonane-2-one; (trans) each ({[1-(2-fluorophenyl)_1Η10 sylvestre]amino} fluorenyl) winter π 20 哒 基 卜 卜 1 oxa 3 azole snail [4·5] Decane-2_one·
基)-3-[5-(三 《(U (2氟本基ΜΗ-吼哇-3-基]胺基}甲 三氟甲基)_3_°比啶基]-1_氧雜-3-氮雜螺[4.5]癸烷 -18. 200838508 -2-酮;Benzyl-3-(5-(tri"(U(2fluorobenyl-indolyl-3-yl)amino}methyltrifluoromethyl)_3_°pyridinyl]-1_oxa-3- Azaspiro[4.5]decane-18. 200838508-2-one;
(反式)-8-({[l-(2-氟苯基)_1H 井基)-im虱雜螺[ο]癸貌如同· (反式)-3-(2,1,3-苯并噻二哇 , 吼嗤冬細基卜甲基)小氧雜3基Μ.#-氟苯基)仙-(反式)-HU-苯并二号茂=^=雜螺⑽癸烧_2-酮; 唑-3-基]絲}甲基)小氧雜^ ({Π·(2^本基)-1H-吡 40 15 20 基)-342-(甲基氧)_5_嘴啶基:坐;基]基}甲 m. 乳雜-3-氮雜螺[4.5]癸烷一 2- (ϋ—Γ ίϋ?1苯基)·1 Η·吼唾·3 -基]胺基}甲基)_3 -(1 _ 乳斗基疋基氧雜_3·氮雜螺[4.5]癸烧_2_酮; (反式)_8-({[1-(2·氟苯基㈣七坐-3·基]胺基丨甲 甲基-3-吼咬基)小氧雜_3_氮雜螺[45]癸烧_2_酉同;土 _ (反式)-8-({[1·(2-氟苯基吨“比哇·3·基擔基 嘧啶基)小氧雜!氮雜螺[4.5]癸烷_2_酮; )(5_ (反式)1({[1-(2-氟苯基基]胺 甲W定基氧雜_3_氮雜螺[4 5]癸烧_2_酮._(5-(反式)-8-({Π-(2-氟苯基HH_nm基]胺 甲W定基H•氧雜_3_氮雜螺[4 5]癸烧_2舞 (6_ (反式)-8·({[ι-(2_氟苯基HH_nm基]胺基}曱 曱基_4』比咬基)小氧雜_3_氮雜螺[45]癸烧_2_酉同; (反式)各({[1-(2-氟苯基)_m_吡唑_3_基]’胺美 基)-3-[6-(甲基氧)_3+定基]小氧雜氮雜螺[45]^^ -19- 200838508 酮; (反式)-8-({[l-(2-氟苯基基]胺基}曱基)_3_(6_ 氟-3』比咬基)_1_氧雜_3_氮雜螺[4·5]癸烷_2_酮; (反式)-8-({[1-(2-氟苯基)_1Η^比唑_3_基]胺基}甲基)_3_咪 唑并[l,2-a]吡啶-6-基氧雜-3-氮雜螺[4.5]癸烷·2-酮; (反式)冬(3_氟冬甲基〜比啶基)_8_({[1_(2_氟苯基比 嗤基]胺基}甲基)_1•氧雜I氮雜螺、[4·5]癸烷j-酮; (反式)-8-({[1-(2-氟苯基)_1Ή_ σ比唑_3基]胺基》甲 基)-3-(1,3-嗔唑_2_基氧雜_3_氮雜螺[4·5]癸烷酮; 4,[三反式氟苯基比唾各基]胺基}甲基峰 側氧-1-氧雜-3-氮雜螺_[4·5]癸-3-基]苯甲腈; 3-[(反式)_8-({[1-(2,氟苯基)_1Η_Π比唾_3_基]胺基}甲基峰 侧氧_1_氧雜-3-氮雜螺-[个5]癸_3_基]苯甲腈; 15 20 3 [(反式)_8·({[1-(2_氟苯基)_1Η』比唾_3_基]胺基}曱基峰 側氧-1-氧雜-3-氮雜螺_[4·5]癸_3_基]苯甲腈; (反式)-8-({[1-(2-氟苯基)_1Η_π比唾3基]胺基}甲基)邻_ 乳-3♦定基)小氧雜_3_氮雜螺[45]癸烧_2_酉同; (反式)-H{[H2-氣苯基胺基 氣苯基MH_m基]胺基}甲基 °坐并4[1叫终3_基小氧雜I氮雜螺[4.5]癸烧_2_酮. (甲反:=/2广苯基咖… ^酮.Μ心定基)小氧雜冬氮雜螺⑽癸 -20- 200838508 (反式)-8-({[1-(2-氟苯基坐基]胺基}甲基)冬(ι_ 甲基-1Η-口米嗤-2-基)-1-氧雜_3_氮雜螺[45]癸烧_2_酉同; (反式)-8-({[1-(2-氟苯基HH』比唾_3_基]胺基}甲基’)_3_(2_ 嘧啶基)-1-氧雜-3-氮雜螺[4.5]癸燒|酮· (反式WUH2-氟苯基HH_吼唾_3_基]胺基}甲基)冬味 峻并[l,2-a]吼咬-7-基-1-氧雜_3_氮雜螺[45]癸烧_2_酉同 (反式)各(2’M-苯并今二哇_5_基)_8_({[H2_氣苯基)_ih_ t坐-3-基]胺基}曱基η-氧雜_3-氮雜螺[4 5]癸烧·2_酉同; (反式)-8_({[1-(2-氟苯基)-lH-D比哇_3_基]胺基}甲基)冬(3_ 曱基-5-兴噻唑基)-1-氧雜-3-氮雜螺[4·5]癸烷_2_酮;(trans)-8-({[l-(2-fluorophenyl)_1H well base)-im虱 snail [ο] looks like · (trans)-3-(2,1,3-benzene噻二二, 吼嗤冬细基卜 methyl)小氧杂3基Μ.#-Fluorophenyl)xian-(trans)-HU-benzodioxin =^=heterospiral (10)癸烧_2- Ketone; oxazol-3-yl]silyl}methyl)oxyxan^({Π·(2^本基)-1H-pyridyl 40 15 20 yl)-342-(methyloxy)_5_ phenidinyl:坐基基基基甲 m. Milkyza-3-azaspiro[4.5]decane-2-(ϋ-Γ ϋ ϋ 11 phenyl)·1 Η·吼 ··3 -yl]amino} Base)_3 -(1 _ 乳 疋 疋 氧 氧 _ 3 3 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 ( ( ( ( ( ( -3·yl]amino-methylmethyl-3-indenyl) small oxa-3_azaspiro[45]癸烧_2_酉同;土_ (trans)-8-({[ 1 ((2-fluorophenyl ton "biwax-3-yl-pyrimidinyl) small oxa! azaspiro[4.5] decane-2 ketone; ) (5_ (trans) 1 ({[1 -(2-fluorophenyl)amine-A-W-based oxa-3-azaspiro[4 5]pyrazine-2_one._(5-(trans)-8-({Π-(2- Fluorophenyl HH_nm group] amine A W group H•oxa _3_aza snail [4 5] 癸 _2 _2 dance (6_ (trans)-8·({[ι-(2_fluorophenyl HH_nm) Amino group] (a) a small oxygen _3_azaspiro[45] sputum _2_ 酉; (trans) each ({[1-(2-fluorophenyl)_m_pyrazole _3_yl]' amine Mesquitin)-3-[6-(methyloxy)_3+定基]小oxa-nitrosospiro[45]^^ -19- 200838508 ketone; (trans)-8-({[l-(2-fluoro) Phenyl]amino}indenyl)_3_(6_fluoro-3) than bityl)_1_oxa_3_azaspiro[4·5]nonane-2_one; (trans)-8- ({[1-(2-Fluorophenyl)_1Η^biazole-3-yl]amino}methyl)_3_imidazo[l,2-a]pyridin-6-yloxa-3-aza Spiro[4.5]decane·2-ketone; (trans) winter (3_fluorobutanyl~pyridyl)_8_({[1_(2_fluorophenyl-indenyl)amino}methyl)_1 • oxaza azaspiro, [4·5]decane j-ketone; (trans)-8-({[1-(2-fluorophenyl)_1Ή_ σ-biazole-3-yl]amino) ))-3-(1,3-oxazol-2-yloxy-3_azaspiro[4·5]nonanone; 4,[tri-transfluorophenyl-saltyl]amine] Methyl peak side oxy-1-oxa-3-azaspiro-[4·5]indol-3-yl]benzonitrile; 3-[(trans)_8-({[1-(2, fluorine) Phenyl)_1Η_Π than salivation_3_yl]amino}methyl peak side oxygen_1_oxa-3-azaspiro-[a 5]癸_3_yl]benzonitrile; 15 20 3 [( Trans)_8·({[1-(2_fluorophenyl)_1Η) is more than saliva_3_ base Amino} fluorenyl peak oxy-1-oxa-3-azaspiro-[4·5] 癸_3_yl]benzonitrile; (trans)-8-({[1-(2 -fluorophenyl)_1Η_π than salin-3-yl]amino}methyl)-o-milk-3♦-fixed) small oxa-3_azaspiro[45]癸烧_2_酉同; (trans)- H{[H2-gasylamino-based gas phenyl MH-m-yl]amino}methyl] sits and 4[1] is the final 3_yloxyxaza azaspiro[4.5]癸2_one. A reverse: = /2 wide phenyl coffee... ^ ketone. Μ心定基) small oxygen heterozygous nitrogen snail (10) 癸-20- 200838508 (trans)-8-({[1-(2-fluorophenyl sitting) Amino]methyl}methanol (ι_methyl-1Η-Methyl-2-yl)-1-oxa-3_azaspiro[45]癸烧_2_酉; (trans) -8-({[1-(2-fluorophenylHH) is more than sal-3-yl]amino}methyl')_3_(2_pyrimidinyl)-1-oxa-3-azaspiro[4.5] Strontium|ketone·(trans-WUH2-fluorophenyl HH_吼Salt_3_yl]amino}methyl) Wintery and [l,2-a] bite-7-yl-1-oxa _3_Azaspiro[45]癸烧_2_酉同(trans) each (2'M-benzo-n-wow_5_yl)_8_({[H2_气phenyl)_ih_ t- 3-yl]amino}indenyl η-oxa-3-azaspiro[4 5]indole·2_酉; (trans)-8_({[1-(2-fluorophenyl)-) lH-D is wow_3_yl]amino}methyl) winter (3_ fluorenyl) 5-5-thiazolyl)-1-oxa-3-azaspiro[4·5]nonane-2-one;
-10 15 20 (反式)冬(2-氟冬曱基冬吼咬基)1({[1|氣苯基ηη』比 嗤-3-基]胺基}-甲基)小氧雜_3_氮雜螺[4·5]癸烷_2_酉同; (反式)1({[1-(2-氟苯基)-11^比唾士基]胺基}甲基普 曱基-5-嘧啶基>1-氧雜-3-氮雜螺[4·5]癸烷_2_酮; (反式)1({[1-(2-氟苯基)_11^比唾_3_基]胺基}曱基)冬(2_ 曱基-ι,3-嘆唾-4-基)小氧雜,3_氮雜螺[4·5]癸烷-2_酮; (反式)-8-({[1-(2-氟笨基)-頂_ σ比唑_3_基]胺基)甲 基)冬[2加氟曱基)_5+定基]小氧雜-3_氮雜螺[4·5]癸烷 -2-酮; (反式)-8-({[1-(2-氟苯基)-imb唑_3_基]胺基}曱基)_3_(2_ 氟-4-吡啶基)-1-氧雜-3-氮雜螺[4·5]癸烷_2_酮; (反式)冬(2,6·:甲基冬吼口定基冰川叩-氟苯基卜他吡 嗤-3-基]胺基}甲基)小氧雜!氮雜螺[4·5]癸烧_2_酮; (反式)ι({[ι-〇氟苯基基]胺基}曱基)_3普 -21 - 200838508 噠p井基)-1 -氧雜-3 -氮雜螺[4·5]癸烧-2-酮; (反式)1({[1-(2-氟苯基)·1Η·吼唑·3_基]胺基}甲基)_3_(5-甲基-1,3,4-噻唑-2-基氧雜_3_氮雜螺[4·5]癸烷_2_酮; (反式)-8-({[1-(2-氟苯基比唑基]胺基}曱基)_3_(3_ 5 吼σ定基)-1 -氧雜_氮雜螺[4·5]癸烧-2·酮; (反式)-8-({[1-(2-氟苯基)-1η_ώ比唑_3_基]胺基}甲基)_3_(ιη_ 吡唑-3-基)-1-氧雜-3-氮雜螺[4·5]癸烷-2-酮; (反式氟苯基比唑-3-基]胺基}甲基)_3_(1Η-暑 吡唑4基)小氧雜_3_氮雜螺μ·5]癸烷_2•酮; -10 (反式氟苯基)-1Η^比唑-3-基]胺基}甲基)_3_(2_ °比σ定基)-1 -氧雜-3·氮雜螺[个5]癸烧_2_酮; 8-氟-8-({[1-(2-氟苯基)_1Η_σ比唑_3_基]胺基丨曱基比 σ定基)-1 -氧雜-氮雜螺[4·5]癸烧-2-酉同; 8-氟-8-({[1-(2-氟苯基)-ΐΗ_吼唑_3一基]胺基}甲基)_3_(2_吼 15 咬基)-卜氧雜氮雜螺[4.5]癸烧_2_酮; (反式)-8-({[1-(2_氟本基)]Η- 〇比tj坐_3_基]胺基》甲 • 基)-3-[1,2,4]三唾并[1,5外比啶-6-基小氧雜_3_氮雜螺[4.5] 癸烷-2-酮; (反式氟苯基比唑-3-基]胺基}甲基 20 甲基-1〇比峻,本基)"1 _氧雜-3 _氮雜螺[4 · 5 ]癸燒-2 -酮; (反式)-8-{[(5_苯基-1H-吡唑-3-基)胺基]曱基}·3_(3-吡啶 基)小氧雜-3-氮雜螺-[4·5]癸烷-2-酮; (順式氟苯基比唑-3-基]胺基}甲基)_3-(3一 口比啶基l·1·氧雜-3-氮雜螺[4·5]癸烷-2-酮; -22- 200838508 1-(2-氟苯基)-3-({[(反式)-2-侧氧-3-(2-吼啶基)-1-氧雜-3-氮 雜螺[4.5]癸-8-基]曱基}-胺基)-1Η-吡唑-4-甲腈; (反式)-8-{[(3-苯基-5-異噚唑基)胺基]甲基}-3-(2-吼啶 基:hi-氧雜-3-氮雜螺[4.5]-癸烷-2-酮; 5 (反式)-3-苯基-8-{[(3-苯基-5-異哼唑基)胺基]曱基}-1-氧雜 -3-氮雜螺[4.5]癸烷-2-酮; 或其藥學上可接受的鹽類、溶劑化物類。 本發明的一具體實施例中,提供下述化合物或其藥學 上可接受的鹽類、溶劑化物類: -10 (反式)-8-({[1-(2-氟苯基)-1Η-吼唑-3-基]胺基}曱基)-3-(2- 氟-3-吼啶基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮; ,(反式)-8-({[1-(2-氟苯基比唑-3-基]胺基}曱基)-3-(3-噠畊基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮; (反式)-8-({[1-(2-氟苯基吼唑-3-基]胺基}曱基)-3-(1-15 曱基-1H-吡唑-3-基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮。 本發明的另一具體實施例中提供具式(IIA)的化合 ® 物,或其一種藥學上可接受的鹽或溶劑化物:-10 15 20 (trans) winter (2-fluoroindazinyl hydrazine) 1 ({[1| gas phenyl ηη" is more than indole-3-yl)amino}-methyl) small oxa _ 3_Azaspiro[4·5]decane_2_酉; (trans)1({[1-(2-fluorophenyl)-11^ than sino]amino}methyl pupro -5-pyrimidinyl>1-oxa-3-azaspiro[4·5]nonane-2-one; (trans)1({[1-(2-fluorophenyl))_11^ ratio Salivation _3_yl]amino} fluorenyl) winter (2_ fluorenyl-ι, 3- sin-4-yl) small oxa, 3-azaspiro[4·5]nonane-2 ketone; (trans)-8-({[1-(2-fluorophenyl)-top_ σ-biazole-3-yl]amino)methyl) winter [2-fluoroindolyl]_5+-based] small oxygen -3_azaspiro[4·5]nonan-2-one; (trans)-8-({[1-(2-fluorophenyl)-imbazole-3-yl]amino}indenyl )_3_(2_fluoro-4-pyridyl)-1-oxa-3-azaspiro[4·5]nonane-2_one; (trans) winter (2,6·: methyl hydrazine Dingji Glacier 叩-Fluorophenyl bepazine-3-yl]amino} methyl) small oxygen! Azaspiro[4·5]癸烧_2_ketone; (trans)ι({[ι-〇fluorophenyl]amino}indenyl)_3P-21 - 200838508 哒p well base)-1 -oxa-3-azaspiro[4·5]oxen-2-one; (trans) 1 ({[1-(2-fluorophenyl)·1Η·carbazole·3]yl) }methyl)_3_(5-methyl-1,3,4-thiazol-2-yloxa-3_azaspiro[4·5]nonane-2_one; (trans)-8-( {[1-(2-Fluorophenylbisazolyl)amino}indenyl)_3_(3_5 吼σ-decyl)-1 -oxa-azaspiro[4·5]indole-2·one; Trans)-8-({[1-(2-fluorophenyl)-1η-indoleazole-3-yl)amino}methyl)_3_(ιη_pyrazol-3-yl)-1-oxa-3 -azaspiro[4.5]nonan-2-one; (trans-fluorophenylpyrazol-3-yl)amino}methyl)_3_(1Η-pyrazole-4-yl)oxyxan-3 _Azaspiro[5]nonane-2•one; -10 (trans-fluorophenyl)-1Η^pyrazol-3-yl]amino}methyl)_3_(2_° ratio σ-based)-1 -oxa-3-azaspiro[5]oxime-2-yl; 8-fluoro-8-({[1-(2-fluorophenyl)_1Η_σ-biazole-3-yl]aminopurine]比 σ 定 base)-1 -oxa-azaspiro[4·5] oxime-2-indole; 8-fluoro-8-({[1-(2-fluorophenyl)-indole-carbazole) _3-yl]amino}methyl)_3_(2_吼15 gnashing base)- oxazapine snail [4.5癸 _2 _2 酮 酮 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 反 ( 反 反 反 反 反 反 反 反 反 反 -8 -8 ( ( ( ( ( ( 1,2,4]tris-[1,5-exopyridin-6-yloxyoxa-3-azaspiro[4.5]decane-2-one; (trans-fluorophenylpyrazole-3- Amino]methyl 20 methyl-1 〇 峻 ,, 本 本) "1 _oxa-3 _azaspiro[4 · 5 ] 癸 2 - ketone; (trans)-8- {[(5-Phenyl-1H-pyrazol-3-yl)amino]indenyl}·3_(3-pyridyl)oxyxo-3-azaspiro-[4·5]nonane-2 -ketone; (cis fluorophenylbisoxazol-3-yl)amino}methyl)_3-(3-mouthpyridinyl l·1·oxa-3-azaspiro[4·5]decane- 2-ketone; -22- 200838508 1-(2-fluorophenyl)-3-({[(trans))-2-oxo-3-(2-acridinyl)-1-oxa-3- Azaspiro[4.5]dec-8-yl]fluorenyl}-amino)-1Η-pyrazole-4-carbonitrile; (trans)-8-{[(3-phenyl-5-isoxazole Amino]methyl}-3-(2-acridinyl:hi-oxa-3-azaspiro[4.5]-nonan-2-one; 5 (trans)-3-phenyl- 8-{[(3-phenyl-5-isoxazolyl)amino]indolyl}-1-oxa-3-azaspiro[4.5]nonan-2-one; or pharmaceutically acceptable thereof Salts, solvates. In a specific embodiment of the present invention, the following compounds or pharmaceutically acceptable salts and solvates thereof are provided: -10 (trans)-8-({[1-(2-fluorophenyl)-1Η) -oxazol-3-yl]amino}mercapto)-3-(2-fluoro-3-acridinyl)-1-oxa-3-azaspiro[4.5]decane-2-one; (trans)-8-({[1-(2-fluorophenylpyrazol-3-yl)amino}indolyl)-3-(3-indolyl)-1-oxa-3-nitrogen Heterospiro[4.5]decane-2-one; (trans)-8-({[1-(2-fluorophenyloxazol-3-yl)amino}indolyl)-3-(1-15 Mercapto-1H-pyrazol-3-yl)-1-oxa-3-azaspiro[4.5]nonan-2-one. In another embodiment of the invention, a compound of formula (IIA) is provided. ® , or a pharmaceutically acceptable salt or solvate thereof:
Η 20 其中 -23- 200838508 R 為一種芳基或雜芳基,其可經一或多個的下述基取代: 鹵素、C1-C4烷基、C1-C4烷氧基、C1-C4鹵基烷基、 C1-C4鹵基烷氧基、氰基; Z! 為Η、C1-C4烷基或F; 5Η 20 wherein -23- 200838508 R is an aryl or heteroaryl group which may be substituted by one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 halo Alkyl, C1-C4 haloalkoxy, cyano; Z! is hydrazine, C1-C4 alkyl or F;
10 Ζ 為 CH2、CH(C1_C4 烷基)、C(C1-C4 烷基)2 或一種鍵 結; Αι 為噻唑,其可經一或多個的下述基取代:鹵素、C1-C4 烷基、C1-C4烷氧基、C1-C4鹵基烷基、C1-C4鹵基 烷氧基、氰基; B 為氫或為一種5-6成員的雜芳基,或苯基,其可經一 或多個的下述基取代:鹵素、C1-C4烷基、C1-C4烷 氧基、C1-C4鹵基烷基、C1-C4鹵基烷氧基、氰基;A 及B可經由任一原子被連結。 1510 Ζ is CH2, CH(C1_C4 alkyl), C(C1-C4 alkyl)2 or a bond; Αι is thiazole which may be substituted by one or more of the following groups: halogen, C1-C4 alkyl , C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano; B is hydrogen or a 5-6 membered heteroaryl, or phenyl, which may be One or more of the following substituents: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano; A and B may be via Any atom is linked. 15
本發明的另一具體實施例中提供具式(IIB)的化合 物,或其一種藥學上可接受的鹽或溶劑化物:In another embodiment of the invention there is provided a compound of formula (IIB), or a pharmaceutically acceptable salt or solvate thereof:
(ΠΒ)(ΠΒ)
其中 R 為一種芳基或雜芳基,其可經一或多個的下述基取代: 鹵素、C1-C4烷基、C1-C4烷氧基、C1-C4鹵基烷基、 -24- 20 200838508 C1-C4鹵基烷氧基、氰基; Ζι 為Η、C1-C4烷基或F; Α2 為吡唑,其可經一或多個的下述基取代:F、a、Br、 C1-C4烷基、C1-C4烷氧基、C1-C4鹵基烷基、CLC4 5 鹵基烧乳基、氧基; B 為氫或為一種5-6成員的雜芳基,或苯基,其可經一 或多個的下述基取代:鹵素、C1-C4烷基、C1-C4烷 氡基、C1-C4 i基烷基、C1-C4鹵基烷氧基、氰基;A ® 及B可經由任一原子被連結。 1〇 本發明的另一具體實施例中提供具式(IIC)的化合 物,或其一種藥學上可接受的鹽或溶劑化物:Wherein R is an aryl or heteroaryl group which may be substituted by one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, -24- 20 200838508 C1-C4 haloalkoxy, cyano; Ζι is hydrazine, C1-C4 alkyl or F; Α2 is pyrazole which may be substituted by one or more of the following groups: F, a, Br, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, CLC4 5 haloalkyl, oxy; B is hydrogen or a 5-6 member heteroaryl, or phenyl , which may be substituted by one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkylthio, C1-C4 alkyl, C1-C4 haloalkoxy, cyano; A ® and B can be linked via any atom. 1) A further embodiment of the invention provides a compound of formula (IIC), or a pharmaceutically acceptable salt or solvate thereof:
(ISC) 其中 15 R 為一種芳基或雜芳基,其可經一或多個的下述基取代: 鹵素、C1-C4烷基、C1-C4烷氧基、C1-C4鹵基烷基、 C1-C4鹵基烷氧基、氰基; A3 為異哼唑,其可經一或多個的下述基取代:鹵素、 C1-C4烷基、C1-C4烷氧基、C1-C4鹵基烷基、C1-C4 鹵基烷氧基、氰基; -25- 20 200838508 B 為氫或為一種5-6成員的雜芳基,或苯基,其可經一 或多個的下述基取代:鹵素、C1-C4烷基、C1-C4烷 氧基、C1-C4鹵基烷基、C1-C4鹵基烷氧基、氰基;A 及B可經由任一原子被連結。 5 通常,式(I)的化合物可根據本領域中的行家所知之有 機化學合成技術被製造,且代表性的方法被出示於實例 中。(ISC) wherein 15 R is an aryl or heteroaryl group which may be substituted by one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl , C1-C4 haloalkoxy, cyano; A3 is isoxazole, which may be substituted by one or more of the following groups: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 Haloalkyl, C1-C4 haloalkoxy, cyano; -25-20 200838508 B is hydrogen or a 5-6 membered heteroaryl, or phenyl, which may be passed through one or more The substituents are: halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano; A and B may be bonded via any atom. 5 In general, the compounds of formula (I) can be made according to organic chemical synthesis techniques known to those skilled in the art, and representative methods are shown in the examples.
式(I)的化合物,以及其鹽類及溶劑化物,可由概述於 ® 後的方法被製備,在下述的說明中,R、Z、Z!、A及B 10 等基團,除非另有說明,具有如同前面式(I)化合物中所給 定義。 圖表 1The compounds of formula (I), as well as the salts and solvates thereof, may be prepared by methods outlined in the following, in the following description, groups such as R, Z, Z!, A and B 10 unless otherwise stated , having the definition given in the compound of the above formula (I). Chart 1
式(Ic)的化合物,相當於其中Z=CH2之式(I)的化合 物,可由式(II)的醛與式(III)的胺,在一種還原劑(例如, 氰基氫硼化鈉、氳硼化鈉或三醋酸基氫硼化鈉)存在下, 選擇地在一種試劑(例如,四異丙氧化鈦、氯-三-異丙氧化 鈦及/或醋酸)存在下,在一種非質子溶劑(例如,二氯曱烷) -26- 20 200838508 内反應而得;式(III)的化合物為可購得之產品,例如,2-胺基-4-(2-吡啶基)噻唑可得自,例如,FluorochemLtd.;2-胺基-5 -苯基 比 _ 可得自 Tokyo Chemical Industry Co., Ltd·,其他的胺類可根據文獻中的方法或類似的方法被製 5 備’例如’ 1-(2-氟苯基唾-3-胺,被揭露於Journal ofA compound of the formula (Ic) corresponding to a compound of the formula (I) wherein Z=CH2, an aldehyde of the formula (II) and an amine of the formula (III), in a reducing agent (for example, sodium cyanoborohydride, In the presence of sodium borohydride or sodium triacetate hydride, optionally in the presence of a reagent (eg, titanium tetraisopropoxide, chloro-tri-isopropoxide, and/or acetic acid), in an aprotic A solvent (for example, dichloromethane) -26- 20 200838508 is obtained by reacting; a compound of the formula (III) is a commercially available product, for example, 2-amino-4-(2-pyridyl)thiazole is available. From, for example, Fluorochem Ltd.; 2-amino-5-phenyl ratio _ available from Tokyo Chemical Industry Co., Ltd., other amines can be prepared according to methods in the literature or the like. ' 1-(2-Fluorophenyl sal-3-amine, disclosed in the Journal of
Organic Chemistry,2005, 70(23),9222-9229 〇Organic Chemistry, 2005, 70(23), 9222-9229 〇
圖表2Chart 2
ίοΊο
m 式(II)的醛類可由氧化式(V)的醇類而被製備,係使用 一種試劑,例如,Dess-Martin過埃烷、樹脂-支撐的IBX 醯胺、DMPX、TPAP或’Swern’氧化條件(草醯氯/二甲亞 颯,在一種胺驗(例如三乙基胺)或Hunig’s驗存在下)進行 反應;式(V)的醇可由式(IV)的酯類,與像是氫化鋁鋰的試 劑,在低於0°c的溫度、在像是THF的非質子溶劑内,進 行還原反應而得。 圖表3m The aldehyde of formula (II) can be prepared by oxidizing an alcohol of formula (V) using a reagent such as Dess-Martin perhexane, resin-supported IBX decylamine, DMPX, TPAP or 'Swern' Oxidation conditions (grass chloride / dimethyl hydrazine, in the presence of an amine test (such as triethylamine) or Hunig's test); the alcohol of formula (V) can be derived from the ester of formula (IV), and The reagent of lithium aluminum hydride is obtained by a reduction reaction at a temperature lower than 0 ° C in an aprotic solvent such as THF. Chart 3
-27- 20 200838508 式(IVa)的酯類可製自一種式(VII)之環氧化物與一種 式(viii)的胺基甲酸酯類,在一種溶劑(例如,HPMA、 DMPU或NMP)内,一種鹼(例如,第三-丁氧化鈉、氳化 納或BEMP)存在下,較佳地係在高於議力的溫度下進行; 式(VI1)的環氧化物可製自一種酮(VI),其為可購得的化學 品’例如,購自Sigma-Aldrich Chemicals,經與三曱基硫 錯埃化物或在非質子溶劑(例如DMSO或乙腈)内之三曱基 硫鏽蛾化物,在一種鹼(例如氫化鈉、第三-丁氧化鉀或 2,8,9-三異丁基_2,5,8,9-四氮雜_1_磷雙環并[3.3.3]十一烷) 存在下進行反應而得;式(VIII)的胺基甲酸酯類為可購得 之化合物’例如,購自 Sigma-Aldrich Chemicals。 圖表4-27- 20 200838508 The ester of formula (IVa) can be prepared from an epoxide of formula (VII) and a urethane of formula (viii) in a solvent (eg, HPMA, DMPU or NMP) In the presence of a base (for example, sodium tributoxide, sodium hydride or BEMP), preferably at a temperature above the force; the epoxide of formula (VI1) can be prepared from a ketone ( VI), which is a commercially available chemical 'for example, purchased from Sigma-Aldrich Chemicals, with trimethylsulfuronium or trisylsulfide moth in an aprotic solvent such as DMSO or acetonitrile In a base (such as sodium hydride, third-butoxide or 2,8,9-triisobutyl-2,5,8,9-tetraaza-l-phosphinobicyclo[3.3.3] The reaction is carried out in the presence of a monoalkyl); the urethane of the formula (VIII) is a commercially available compound 'for example, available from Sigma-Aldrich Chemicals. Chart 4
式(IVa)的酯類可由式(X)的酯類與一種式(XI)之芳基 或雜芳基鹵化物被製備,適當的反應條件被揭露於: ‘Metal-Catalyzed Cross-Coupling Reactions (2nd Edition)1, 20 2004,2,699-760; Angewandte Chemie,InternationalEsters of formula (IVa) can be prepared from esters of formula (X) with an aryl or heteroaryl halide of formula (XI), and suitable reaction conditions are disclosed in: 'Metal-Catalyzed Cross-Coupling Reactions ( 2nd Edition) 1, 20 2004, 2, 699-760; Angewandte Chemie, International
Edition,2003, 42(44),5400-5449 及其中的參考資料;式 (XI)之芳基或雜芳基鹵化物為可購得之化合物,例如,購 -28- 200838508 自 Sigma-Aldrich Chemicals;式(X)的酯類可製自式(VII) 之一種環氧化物與式(IX)之胺基甲酸酯類,係在一種溶劑 (例如,HPMA、DMPU或NMP)内,在一種驗(例如,第三 胃丁氧化鉀、氫化鈉或BEMP)存在下,較佳地係在高於 l〇〇°C的溫度下進行;式(IX)之胺基甲酸酯類為可購得之化 合物,例如,購自 Sigma·Aldricli Chemicals。Edition, 2003, 42(44), 5400-5449 and references therein; aryl or heteroaryl halides of formula (XI) are commercially available compounds, for example, from -28 to 200838508 from Sigma-Aldrich Chemicals The ester of the formula (X) can be prepared from an epoxide of the formula (VII) and a carbamate of the formula (IX) in a solvent (for example, HPMA, DMPU or NMP) in a test (for example, in the presence of a third stomach potassium butoxide, sodium hydride or BEMP), preferably at a temperature above 10 ° C; the carbamates of formula (IX) are commercially available Compounds, for example, are available from Sigma Aldricli Chemicals.
脚) 《輯 ίο 15 或者,式(IVa)的酯類可製自式(XII)的胺基-醇類與一 種試劑,例如,光氣、三光氣、魏基二-咪α坐、二號珀亞 酸胺基碳酸酯、二氧化竣、一種烧基氯曱酸醋(例如,苯 甲基氯曱酸酯或乙基氯曱酸酯)、一種芳基氯曱酸酯(例 如,笨基氯曱酸酯)或一種二烷基焦碳酸酯(例如,二-第三 -丁基二碳酸酯(Boc酸酐),選擇地在一種鹼(例如三乙基胺) 存在下,在一種溶劑(例如二氯曱烧)内進行;式(XII)的胺 基-醇類可製自式(VII)的一種環氧化物與式(XIII)的胺 類,在一種質子溶劑(例如第三-丁醇或乙氧基乙醇)内,於 高於100°c的溫度下進行;式(ΧΠΙ)的胺類,例如,苯胺, 為可購得之化合物,例如,購自Sigma-Aldrich Chemicals。 y Lm-K 3 / -29- 20 200838508 圖表 6Foot) "According to ίο 15 or, the ester of formula (IVa) can be prepared from the amine-alcohol of formula (XII) with a reagent, for example, phosgene, triphosgene, Weiji di-mi-α sitting, number two Amino acid carbonate, cerium oxide, a chlorinated chloroacetic acid vinegar (for example, benzyl chloro phthalate or ethyl chloro phthalate), an aryl chloro phthalate (for example, a stupid base) Chlorophthalate) or a dialkyl pyrocarbonate (eg, di-tertiary-butyl dicarbonate (Boc anhydride), optionally in the presence of a base (eg, triethylamine), in a solvent ( For example, in the case of dichlorohydrazine; the amine-alcohol of formula (XII) can be prepared from an epoxide of formula (VII) and an amine of formula (XIII) in a protic solvent (eg, third-but In an alcohol or ethoxyethanol), it is carried out at a temperature higher than 100 ° C; an amine of the formula (ΧΠΙ), for example, aniline, is a commercially available compound, for example, from Sigma-Aldrich Chemicals. y Lm -K 3 / -29- 20 200838508 Chart 6
mm
式(XV)的醛類可由氧化式(XIV)的醇類而被製備,係 使用一種試劑’例如,Dess-Martin過埃烧、樹脂·支樓的 IBX觚胺、DMPX、TpAP或’Swern’氧化條件(草醯氯/二甲 亞颯’在一種胺鹼(例如三乙基胺)或Hunig’s鹼存在下)進 行反應;式(χΐν)的醇可由式(χ)的酯類,與像是氫化鋁鋰 的試劑,在低於〇°C的溫度、在像是THF的非質子溶劑内, 進行返原反應而得。 圖表7The aldehyde of formula (XV) can be prepared by oxidizing an alcohol of formula (XIV) using a reagent 'for example, Dess-Martin, IBX guanamine, DMPX, TpAP or 'Swern' The oxidizing conditions (Grass chloroform / dimethyl hydrazine) are carried out in the presence of an amine base (for example, triethylamine) or Hunig's base; the alcohol of the formula (χΐν) may be an ester of the formula (χ), and The reagent for lithium aluminum hydride is obtained by performing a reversion reaction in an aprotic solvent such as THF at a temperature lower than 〇 ° C. Chart 7
式(XVI)的化合物,可由式(XV)的醛類與式(III)的胺 類’在一種還原劑(例如,氰基氫硼化鈉、氫硼化鈉或三 醋酸基氫硼化鈉)存在下,選擇地在一種試劑(例如,四異 丙氧化鈦、氯-三-異丙氧化鈦及/或醋酸)存在下,在一種 非質子溶劑(例如,二氯曱烷)内反應而得;式(III)的化合 -30· 200838508 物為可講得之產品’例如’ 2-胺基-4-(2-0比0定基)坐可得 自,例如,Fluorochem Ltd·; 2-胺基-5-苯基吼喷可得自 Tokyo Chemical Industry Co·, Ltd·,其他的胺類可根據文 獻中的方法或類似的方法被製備,例如,1-(2-氟苯基)_1H-5 吼唾-3-胺,被揭露於 Journal of Organic Chemistry,2005, 70(23),9222-9229。 圖表8a compound of the formula (XVI) which can be obtained from an aldehyde of the formula (XV) and an amine of the formula (III) in a reducing agent (for example, sodium cyanoborohydride, sodium borohydride or sodium triacetate borohydride) In the presence of a reagent (eg, tetraisopropoxide, chloro-tri-isopropoxide, and/or acetic acid), reacted in an aprotic solvent (eg, dichloromethane) The compound of formula (III) -30· 200838508 is a product that can be said to be 'for example, '2-amino-4-(2-0 is 0-based) sitting, for example, Fluorochem Ltd.; 2- Amino-5-phenylindole can be obtained from Tokyo Chemical Industry Co., Ltd., and other amines can be prepared according to methods in the literature or the like, for example, 1-(2-fluorophenyl)_1H. -5 Indole-3-amine, disclosed in Journal of Organic Chemistry, 2005, 70(23), 9222-9229. Chart 8
1〇 om ⑽ 0 式(Id)的化合物,相當於式(Ic)的化合物,其中Ζ^Η 者,可由式(XVI)的化合物與式(XI)的一種芳基鹵化物製 備,適當的反應條件被揭露於:‘Metal-Catalyzed 15 Cross-Coupling Reactions (2nd Edition)、2004, 2,699-760;1 〇 om (10) 0 A compound of the formula (Id) corresponding to a compound of the formula (Ic), wherein the compound can be prepared from a compound of the formula (XVI) and an aryl halide of the formula (XI), suitably reacted. Conditions are disclosed in: 'Metal-Catalyzed 15 Cross-Coupling Reactions (2nd Edition), 2004, 2, 699-760;
Angewandte Chemie5 International Edition, 2003,42(44), 5400-5449及其中的參考資料;式(XI)之芳基鹵化物類為 可購得之化合物,例如,購自Sigma-AldrichChemicals。 20 圖表9 -31- 200838508Angewandte Chemie 5 International Edition, 2003, 42 (44), 5400-5449 and references therein; aryl halides of formula (XI) are commercially available compounds, for example, from Sigma-Aldrich Chemicals. 20 Chart 9 -31- 200838508
imIm
式(iVb)的酯類可製自式(IVa)的酯類,係在一種非質 子溶劑(例如THF)内’經一種驗,例如,二異丙基酿胺化 & 鋰或六甲基二矽疊氮化鈉處理,接著與其中Z2=C1-C4烷 基之式(XVII)的烷基鹵化物反應而得;式(XVII)的鹵化物 為可講得之化合物,例如,購自Sisma-Aldrich Chemicals。 圖表1〇 10Esters of formula (iVb) can be prepared from esters of formula (IVa) by an assay in an aprotic solvent such as THF, for example, diisopropyl alanine & lithium or hexamethyl Treatment with diazide sodium, followed by reaction with an alkyl halide of formula (XVII) wherein Z 2 = C 1 -C 4 alkyl; a halide of formula (XVII) is a derivable compound, for example, purchased from Sisma-Aldrich Chemicals. Chart 1〇 10
式(IVc)的酯類可製自式(IVa)的酯類,係在一種非質子 溶劑(例如THF)内,經一種驗,例如,二異丙基酸胺化經 15 或六甲基二矽疊氮化鈉處理’接著以一種親電子氟化劑 (例如,Selectfluor或N-氟苯磺醯胺)處理而得,親電子的 氟化劑為可購得之化合物,例如,購自Sigma-Aldrich Chemicals 〇 -32- 200838508 圖表11The ester of formula (IVc) can be prepared from an ester of formula (IVa) in an aprotic solvent (eg THF) by a test, for example, amination of diisopropyl acid via 15 or hexamethyl Sodium azide treatment is followed by treatment with an electrophilic fluorinating agent (eg, Selectfluor or N-fluorobenzenesulfonamide), which is a commercially available fluorinating agent, for example, purchased from Sigma. -Aldrich Chemicals 〇-32- 200838508 Chart 11
(XVU!) φ 式(Id)的化合物,相當於式(1)的化合物,其中 5 Z二CH(C1-C4烷基)且Z^H者,可由式(XVIII)的化合物與 式(XIX)的一種Grignard試劑,其中Z2=C 1-C4烷基,在一 種非質子溶劑(例如,THF)内反應而得;式(XVIII)的化合 物可藉由混合式(II)’的醛類(其為相當於式(II)的化合物, 其中ZfH者)與式(III)的胺類,在苯并三唑存在下,於一 10 種非質子溶劑(例如曱苯)内,較佳地在高於室溫下進行反 應而得;式(III)的化合物為可購得之產品,例如,2-胺基 ⑩ -4-(2_吼口定基)口塞嗤可得自,例如,FluorochemLtd·; 2-胺美 -5-苯基吼σ井可得自 Tokyo Chemical Industry Co.,Ltd,其 他的胺類可根據文獻中的方法或類似的方法被製借,例 15 如,1-(2-氟笨基)_1H-吡唑-3-胺,被揭露於J〇Unial μ(XVU!) φ A compound of the formula (Id) corresponding to a compound of the formula (1) wherein 5 Z is di-CH(C1-C4 alkyl) and Z^H, which may be a compound of the formula (XVIII) and a formula (XIX) a Grignard reagent in which Z2=C1-C4 alkyl is obtained by reaction in an aprotic solvent (for example, THF); a compound of formula (XVIII) can be obtained by mixing an aldehyde of the formula (II) ( It is a compound corresponding to the formula (II), wherein ZfH) and the amine of the formula (III) are in the presence of benzotriazole in one of 10 aprotic solvents (for example, toluene), preferably The reaction is carried out at room temperature; the compound of the formula (III) is a commercially available product, for example, 2-amino 10 -4-(2 吼 定 定 ) 口 口 嗤 嗤 嗤 嗤 嗤 嗤, for example, Fluorochem Ltd · 2-Amino-5-phenylindole σ well available from Tokyo Chemical Industry Co., Ltd. Other amines can be borrowed according to methods in the literature or similar methods, such as 15-(1) 2-Fluorophenyl)_1H-pyrazol-3-amine, disclosed in J〇Unial μ
Organic Chemistry,2005, 70(23),9222-9229。 本技藝的行家了解,在製備本發明的化合物時,可& 有需要及/或有必要去保護涉及反應的分子上之一或多= 敏感的基以避免不想要的副反應,被使用在根據本發明 20 適Μ的保護基為本技藝中的行家所熟悉者且可以傳纟先方 -33- 200838508 式被應用,見,例如,’’Protective groups in organic synthesis11 by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991)或’’Protecting Groups” by RJ· Kocienski (Georg Thieme Verlag 1994),適當的胺基保護基的實例包括醯基 5 類型的保護基類(例如,曱醯基、三氟乙醯基、乙醯基)、 芳族的胺基甲酸酯保護基類(例如,苯曱基氧羰基(Cbz)及 經取代的Cbz)、脂肪族的胺基甲酸酯保護基類(例如,9-苐基甲氧基羰基(Fmoc)、第三-丁氧基羰基(Boc)、異丙氧 基羰基、環己氧基羰基)及烷基類型之保護基(例如,苯甲 ίο 基、三苯曱基、氯三苯甲基)。 本發明的目的也包括以同位素標記之化合物類,其為 相同於那些式(I)中被述及的化合物,但是其中有一或多個 原子被取代成原子量或原子序為不同於通常為出現在天 然物中之原子量或原子序者,可被加入至本發明的化合物 15 及其藥學^可接受的鹽類内之同位素的實例包括氫、碳、 氮、氧、磷、硫、氟、碘、及氯等之同位素,例如,2H、 • 3H、UC、13C、14c、、、17〇、18〇、31p、32p、35s、18f、 36q、U3I、〇 含有上述同位素及/或其他的原子之其他同位素之本 20 #明的化合物被涵蓋於本發明的範圍之内,經同位素-標 記的本發明的化合物,例如那些加人了放射活性的同位 夸,例如’ Η、 ^ 、 者,為有用於藥物及/或受質組織分佈 分析者尤其u為氣(即,如與碳·叫即,同位素, 係由於其容易製備及债測,uc及18f同位素特別有用於 -34- 200838508 ΡΕΤ(正子斷層造影),而i25j同位素特別有用於spECT (單 光子激發電腦斷層造影),均有用於大腦影像之造影,式夏 且根據本發明之經同位素標記之化合物通常可根據下述 的圖表及/或實例中描述的程序製備,係藉由以容易地取 得之經同位素標記的試劑替代非經同位素標記的試劑進 行反應而得。 本發明的化合物為NPYY5受體之拮抗劑,並因此為 有用於供防止及治療與NPYY5受體子型相關的疾病及不 舒服之樂劑’較佳地係用於治療飲食異常,例如,肥胖、 厭食症及暴食症,以及其他不正常的狀況,例如,糖尿病、 高企壓、高脂血、高膽固醇、充血性心臟衰竭、腎臟功能 不良、性/生殖功能失調、憂鬱、焦躁、中風、癲癇症發 作、記憶損失、睡眠干擾、痛苦、偏頭痛、腦溢血、鼻充 血、腸胃失調、關節炎及免疫缺乏症候群。 本發明的化合物也被併用其他的抗-肥胖劑使用,以便 增加預防及治療飲食不正常方面之效力,這類藥劑包括, 但非限於:諾美婷(sibutramine)、右旋芬氟拉明 (dexfenfluramine)、體痩素(leptin)、生長激素分泌刺激素 拮抗劑類,例如那些被描述且明確地被揭露於US Patent 5,536,716中者;黑素皮質素(melanocortin)拮抗劑類,例 如,elanotan II; Beta-3激動劑類,例如那些被揭露及明確 地被說明於專利公告W094/18161、W095/29159、 W097/46556、WO98/04526 及 W098/32753 中者;5HT-2 激動劑類;食慾激素拮抗劑類;黑色素濃縮激素拮抗劑類; -35- 200838508 苷丙胺激素(galanin)拮抗劑類;CCK激動劑類;GLP-l激動 劑類;促腎上腺皮質激素釋放激素激動劑類;Yl拮抗劑類; 及CB1拮抗劑類。 更明確地說,本發明的化合物有用於作為一種藥劑供 5 治療及/或預防飲食方面的疾病,例如,狂吃症。 本發明的治療方法包括拮抗NPY Y5受體以及處理 NPY Y5受體媒介的疾病的方法,係藉由對有需要此種治 療的患者投與一種無毒性的、具治療效果量的、相較於其 _ 他NPY受體類為具有優先選擇地拮抗NPY Y5受體之本 ίο 發明的化合物。 本發明的内文中,所用於描寫一些徵狀的專有名詞被 分類在精神疾病的診斷與統計指南(Diagnostic andOrganic Chemistry, 2005, 70(23), 9222-9229. It is understood by those skilled in the art that in the preparation of the compounds of the present invention, it is desirable and/or necessary to protect one or more of the molecules involved in the reaction = sensitive groups to avoid unwanted side reactions, According to the present invention, 20 suitable protecting groups are familiar to those skilled in the art and can be used as described in the formula -33-200838508, see, for example, ''Protective groups in organic synthesis11 by TW Greene and PGM Wuts (John Wiley & sons 1991) or ''Protecting Groups' by RJ Kocienski (Georg Thieme Verlag 1994), examples of suitable amine protecting groups include protecting groups of the thiol 5 type (eg, fluorenyl, trifluoroethyl) Sulfhydryl, ethyl fluorenyl), aromatic urethane protecting groups (for example, benzoyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane protecting groups (eg , 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), isopropoxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protecting groups (eg, benzoic acid) , triphenyl fluorenyl, chlorotrityl). The invention The object also includes isotopically labeled compounds which are the same as those recited in formula (I), but in which one or more atoms are substituted into atomic weight or atomic order is different from that which is usually found in natural materials. Examples of the atomic weight or atomic sequence which can be added to the compound 15 of the present invention and its pharmaceutically acceptable salt include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. Isotope, for example, 2H, • 3H, UC, 13C, 14c, 17, 17〇, 18〇, 31p, 32p, 35s, 18f, 36q, U3I, 〇 containing other isotopes of the above isotopes and/or other atoms The compounds of the present invention are encompassed within the scope of the present invention, and the isotope-labeled compounds of the present invention, such as those having a radioactive ortho-communication, such as 'Η, ^, are used for the drug and / or the texture of the tissue distribution analysis, especially u is gas (ie, as with carbon, called isotope, because of its easy preparation and debt testing, uc and 18f isotopes are particularly useful for -34-200838508 ΡΕΤ (positive tomography) , The i25j isotope is particularly useful for spECT (single photon-excited computed tomography), both for imaging of brain imaging, in the summer and isotopically labeled compounds according to the invention, generally according to the procedures described in the following diagrams and/or examples The preparation is carried out by replacing the non-isotopically labeled reagent with an easily obtained isotope-labeled reagent. The compounds of the present invention are antagonists of the NPYY5 receptor and are therefore useful for the prevention and treatment of diseases and discomfort associated with the NPYY5 receptor subtype', preferably for the treatment of dietary abnormalities, for example, obesity , anorexia and bulimia, and other abnormal conditions, such as diabetes, high blood pressure, hyperlipemia, high cholesterol, congestive heart failure, kidney dysfunction, sexual/genital dysfunction, depression, anxiety, stroke, epilepsy Symptoms, memory loss, sleep disturbance, pain, migraine, cerebral hemorrhage, nasal congestion, gastrointestinal disorders, arthritis and immunodeficiency syndrome. The compounds of the present invention are also used in combination with other anti-obesity agents to increase the effectiveness of preventing and treating disorders in the diet, including, but not limited to, sibutramine, dexfenfluramine ( Dexfenfluramine), leptin, growth hormone secreting stimulating hormone antagonists, such as those described and specifically disclosed in US Patent 5,536,716; melanocortin antagonists, for example, elanotan II Beta-3 agonists, such as those disclosed and specifically described in Patent Publications W094/18161, W095/29159, W097/46556, WO98/04526, and W098/32753; 5HT-2 agonists; appetite Hormone antagonists; melanin concentration hormone antagonists; -35- 200838508 glucosamine hormone (galanin) antagonists; CCK agonists; GLP-1 agonists; corticotropin releasing hormone agonists; Yl antagonist Agents; and CB1 antagonists. More specifically, the compounds of the present invention are useful as a medicament for the treatment and/or prevention of diseases in the diet, for example, madness. The method of treatment of the present invention comprises a method of antagonizing the NPY Y5 receptor and treating a disease of the NPY Y5 receptor vector by administering to a patient in need of such treatment a non-toxic, therapeutically effective amount compared to Its NPY receptor class is a compound of the invention which preferentially antagonizes the NPY Y5 receptor. In the context of the present invention, the proper nouns used to describe some symptoms are classified into diagnostic and statistical guidelines for mental illness (Diagnostic and
Statistical Manual of Mental Disorders),4th Edition, published by the American Psychiatric Association 15 (DSM-IV)及/或 the International Classification of Diseases, 10th Edition (ICD-10)中,在此被提及的疾病之各種子型均 鲁 意圖當作本發明之一部分,在下面列出的疾病後面括弧内 之數字相當於DSM-IV中之分類代碼。 憂鬱症及情緒困擾包括重鬱發作、躁症發作、混合的 2〇 發作及輕躁症發作;憂鬱症包括重鬱症(Major DepressiveStatistical Manual of Mental Disorders), 4th Edition, published by the American Psychiatric Association 15 (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10), the various diseases mentioned here. Types are intended to be part of the invention, and the numbers in parentheses following the diseases listed below correspond to the classification codes in DSM-IV. Depression and emotional distress include severe seizures, snoring episodes, mixed episodes of seizures and episodes of palsy; depression includes major depressive disorders (Major Depressive)
Disorder)、輕鬱症(3〇〇·4)、未予以確認之憂鬱症(311);其 他的情緒困擾症包括··身體疾病相關之情緒困擾 (293·83) ’其包括具憂鬱症特徵、具類-重鬱症發作、具躁 症發作及具混合的特徵之子型),物質_誘發的情緒困擾(包 -36- 200838508 括具憂鬱症特徵、具躁症發作及具混合的特徵之子型)以 及未予以確認之情緒困擾(296.90); 焦慮症類包括恐慌發作;恐慌症包括未伴隨懼曠症 之恐慌症(300.01)及伴隨懼曠症之恐慌症(3〇〇 21);懼曠 症;未冒有過恐慌症之懼曠症(3〇〇·22);特定恐懼症 (300.29,從前稱之為單純恐懼症)包括下類子型:動物^Disorder), mild depression (3〇〇·4), unconfirmed depression (311); other emotional distresses include · emotional disorders associated with physical illness (293·83) 'which includes depression characteristics, Class--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- And unrecognized emotional distress (296.90); anxiety disorders including panic attacks; panic disorder including panic disorder without fear of delirium (300.01) and panic disorder with fear of delirium (3〇〇21); fear of snoring Not afraid of panic disorder (3〇〇22); specific phobia (300.29, formerly known as simple phobia) includes the following subtypes: animals^
-10 15 20 型、天然環境類型、血液-注射_傷害類型、情境類型及其 他類型)、社交恐懼症(社交焦慮症,3〇〇·23)、強迫症 (3〇〇·3)、創傷後壓力症(3〇9·81)、急性壓力症⑽·3)、廣 泛性焦慮症(300.02)、因一般健康狀態引起之焦慮= (293.84)、物質誘發的焦慮症、分離焦慮症(3()9 2丨= 障礙伴隨焦慮_·24)以及未予以確認之焦慮症Ο⑽〇〇^ 物質-相關的疾病包括物質使用疾病類,例如,物 賴性、物質渴求及物質濫用;物㈣發的疾病類,例如: :質中毒、物質戒斷、物質,發的譫妄、物質、誘發的持 =癡呆、物質-誘發的持續失憶症、物質,發的精神病、 物貝-誘發的情緒困擾、物質_誘發的焦慮症、 ,、物質-誘發的睡眠疾病、及迷幻劑持續性知覺工 吊,閃回;酒精-相關的疾病類有如,酒精依賴性(规、 ==Γ·00)、酒精中毒 酒ΐ 戒斷譫妄、酒精·誘發的持續癡呆症、 :縣w、,失,症、酒精·誘發的精神病、酒精_誘發 胖mw 慮喃’發的性無能、 精.賴崎糾未Μ以日峻齡勝相關的 -37- 200838508 疾病(291.9);安非入 類,例如,安非仙他命(或類-安非他命)-相關的疾病 (305.7〇)、安非他合/主依賴性(3〇4.40)、安非他命濫用 安非他命中毒鱗玄卩:(292·89)、安非他命戒斷(292.0)、 誘發的情緒困;二:非他命-誘發的精神病、安非他命- 發的性無能、二:人他命,發的焦慮症、安非他命-誘 確定義的安非他} /ρ·誘發的睡眠疾病以及未另予以明 症、咖啡因千巾母 〇)、咖啡因_誘發的焦慮 因-相關的疾病類另予以明確定義㈣ 麻依賴性(3〇43〇U广 麻相關的疾病類,例如,大 A#, t A " (3〇5*2〇)' " *^292·89) ' 以及夫ΐΐ 誘發的精神病、大麻·誘發的焦慮症、 卡w ^以明確疋義的大麻-相關的疾病類(292.9);可 15 20 、可卡因中毒(292 89)、可卡因戒斷 (9=)、可卡因中毒譫妄、可卡因_誘發的精神病、可卡 口-着發的情緒困擾、可卡因-誘發的焦慮症、可卡因_誘發 白、性焦能、可卡因·誘發的睡眠疾病以及以及未予以讀認 之可卡SM目關的疾病(292.9);迷幻劑_相關的疾病類,例 如二迷幻劑依賴性(304.50)、逑幻劑濫用(3〇5 3〇)、迷幻劑 中毒(292.89)、迷幻劑持續性知覺失常(閃回)(292 89)、迷 7月丨中·#»詹妄、迷幻劑-誘發的精神病、迷幻劑-誘發的情 緒困擾、迷幻劑-誘發的焦慮症以及未予以確認之迷幻劑_ 相關的疾病(292.9);吸入劑-相關的疾病類,例如,吸入-10 15 type 20, natural environment type, blood-injection_injury type, situation type and other types), social phobia (social anxiety disorder, 3〇〇23), obsessive-compulsive disorder (3〇〇·3), trauma Post-stress syndrome (3〇9·81), acute stress disorder (10)·3), generalized anxiety disorder (300.02), anxiety due to general health status = (293.84), substance-induced anxiety disorder, separation anxiety disorder (3 () 9 2丨 = dysfunction with anxiety _·24) and unrecognized anxiety disorder 10 (10) 〇〇 ^ substance-related diseases including substance use diseases, for example, material dependence, material craving and substance abuse; Diseases, such as: quality poisoning, substance withdrawal, substance, sputum, substance, induced holding = dementia, substance-induced persistent amnesia, substance, mental illness, scallop-induced emotional distress, Substance_induced anxiety, , substance-induced sleep disorders, and hallucinogen persistence perception, flashback; alcohol-related diseases such as alcohol dependence (regulation, ==Γ·00), Alcoholism, alcoholism, withdrawal, alcohol, induced persistent dementia, : County w,, loss, syndrome, alcohol-induced psychosis, alcohol _ induced fat mw 喃 ' 发 发 性 性 性 、 、 、 、 赖 赖 赖 赖 赖 赖 赖 赖 赖 赖 赖 赖 - - - - - - - - - - - - - - - - - - - - - - - - An amphibious class, for example, Amphetamine (or amphetamine-related disease) (305.7〇), amphetamine/main dependence (3〇4.40), amphetamine abuse amphetamine poisoning scales: (292·89), amphetamine withdrawal (292.0), induced emotional distress; second: non-life-induced psychosis, amphetamine-induced sexual incompetence, two: human life, anxiety, amphetamine-induced The righteous Anghe} / ρ · induced sleep disease and no other symptoms, caffeine thousands of female baboons), caffeine _ induced anxiety caused by the related diseases are clearly defined (four) hemp dependence (3) 〇43〇U 麻-related diseases, for example, big A#, t A " (3〇5*2〇)' " *^292·89) ' and husband-induced psychosis, marijuana-induced anxiety Symptoms, card w ^ to clear the marijuana-related diseases (292.9); can 15 20, cocaine poisoning (292 89), cocaine Broken (9=), cocaine poisoning, cocaine _ induced psychosis, cocaine-emotional distress, cocaine-induced anxiety, cocaine _ induced white, sexual coke, cocaine-induced sleep disorders, and Diseases that are not read by the cocaine SM (292.9); hallucinogens _ related diseases, such as two hallucinogen dependence (304.50), scorpion abuse (3〇5 3〇), psychedelic Agent poisoning (292.89), LSD persistent perceptual disorder (flashback) (292 89), fan July 丨中·#»詹妄, hallucinogen-induced psychosis, hallucinogen-induced emotional distress, LSD-induced anxiety disorders and unrecognized hallucinogens _ related diseases (292.9); inhalants-related diseases, for example, inhalation
-38- 200838508 劑依賴性(304.60)、吸入劑濫用(3〇5 (靡)、吸入劑中毒讀妄、吸入劑,發)二二, 吸入劑-誘發的精神病、吸入 、拭貝卜癡呆、 (292 9).尼*丁 f 相關的疾病 30” ’ 3 的疾病類,例如,尼古丁依賴性 (.)、尼古丁戒斷(292.0)以及未予以確認之尼古丁 關的疾病(292.9);鴆片·相關的疾病,例如鳥 性 (,、鴆片濫用(305.50)、鴉片中毒 15 20 '鵪片中毒讀妄、搗片_誘發的精神病、鴻片-誘 =的1困擾、鴆片·誘發的性無能、鴆片_誘發的睡眠疾 ’丙以及予以確認之鴉片_相關的疾病Ο%.$ ;苯環利定 (或類-苯環利定)·相關的疾病,例如,苯環利定依賴性 (=.60)、苯環利定濫用⑽揭、苯環利定中毒(292別)、 苯環利定中毒譫妄、笨環利定_誘發的精神病、苯環利定_ 誘發的情緒困擾、苯環利定.誘發的焦慮症以及未予以確 認之苯環利定-相關的疾病(292.9);鎮靜劑_、安眠藥_、或 抗焦慮劑-相關的疾病類,例如,鎮靜劑、安眠藥、或抗 焦慮劑依賴性(304.10) ’鎮靜劑、安眠藥、或抗焦慮劑濫 用〇〇5·4〇)、鎮靜劑、安眠藥、或抗焦慮劑中毒(Μ2.89), 鎮靜劑、安眠藥、或抗焦慮劑戒斷(292 〇)、鎮靜劑、安眠 樂、或抗焦慮劑中毒譫妄,鎮靜劑、安眠藥、或抗焦慮劑 戒斷譫妄,鎮靜劑-、安眠藥_、或抗焦慮劑_持續性癡呆, 鎮靜劑-、安眠藥-、或抗焦慮劑-持續失憶症’鎮靜劑_、 女眠樂-、或抗焦慮劑-誘發的精神病、鎮靜劑_、安眠藥_、 -39- 200838508 或抗焦慮劑-誘發的情緒困擾,鎮靜劑-、安眠藥-、或抗 焦慮劑-誘發的焦慮.症,鎮靜劑-、安眠藥-、或抗焦慮劑-誘發的性無能,鎮靜劑-、安眠藥-、或抗焦慮劑-誘發的 睡眠疾病以及未予以確認之鎮靜劑-、安眠藥-、或抗焦慮 5 劑-相關的疾病(292.9);多種藥物-相關的疾病,例如,多 種藥物依賴性(304.80);以及其他(或未知的)藥物-相關的 疾病類,例如,合成代謝類固醇、硝酸鹽吸入劑及氧化 亞氮; 睡眠疾患類包括原發性睡眠障礙,例如,睡眠異常, 40 例如原發性失眠症(307.、42)、原發性嗜睡症(307.44)、猝睡 症(347)、與呼吸相關的睡眠疾患(780.59)、晝夜節律性睡 目民疾患(307.45)以及未予以確認之睡眠異常·相關的疾病 (307.47);原發性睡眠障礙,例如,夢魘症(307.47)、睡眠 驚恐疾患(307.46)、夢遊症(307.46)以及未予以確認之異睡 15 症-相關的疾病(307.47);與其他精神疾病相關之睡眠疾 患,例如,與其他精神疾病相關之失眠症(307.42)以及與 • 其他精神疾病相關之嗜睡症(307.44);身體疾病造成之睡 眠疾患;以及物質-誘發之睡眠疾患,包括下類子型:失眠 類型、嗜睡類型、異睡症類型及混合的類型; 2〇 飲食異常,例如,厭食症(307.1)包括下類子型:禁食 型及狂吃/清除型;暴食症(307.51)包括下類子型:清除 型及非清除型;肥胖··強迫性飲食疾患;狂吃;以及未予 以確認之飲食異常-相關的疾病(307.50); 性功能障礙包括性慾障礙,例如,低性慾障礙 -40- 200838508 (302.71)、及性嫌惡障礙(302.79);性興奮障礙,例如, 女性性冷感(302.72)及男性勃起障礙(3〇2·72);高潮障 礙,例如,女性高潮障礙(3〇2·73);男性高潮障礙(3〇2.74) 以及早洩(302.75);性疼痛障礙,例如,性交疼痛(3〇2·76) 5 及陰道痙攣症(306·51);其他未予以確認之性功能障礙 (3〇2·70);性反常行為,例如,露陰癖(3〇2·4)、戀物癖 (302.81)、挨擦癖(302.89)、戀童癖(302.2)、受虐癖 (302.83)、性盧癖(302.84)、扮異性戀物癖(3〇2·3)、窺淫癖 馨 (302.82)以及其他未予以確認之性反常行為(3〇2 9);性別 10 認同疾患,例如,孩童性別認同疾患(302.6)及青少年或成 人性別認同疾患(302.85);以及其他未予以確認之性慾障 礙(302.9); 本發明另一具體實施例中,提供式⑴化合物、或其藥 學上可接受的鹽或溶劑化物,用於製備供治療狂吃症的醫 15 樂品之用途。 本發明另一具體實施例中,提供治療患有狂吃症的哺 # 礼類的一種方法,係包括向所述對象施用有效量之式⑴ 化合物或其藥學上可接受的鹽或溶劑化物。 爲本發明另一具體實施例中,提供式⑴化合物、或其藥 20 學上可接受的鹽或溶劑化物,用於製備供治療肥胖的醫孳 品之用途。 _ y /来本I明另一具體實施例中,提供治療患有肥胖症的哺 乳頒的一種方法,係包括向所述對象施用有效量之式⑴ 化合物或其藥學上可接受的鹽或溶劑化物。 200838508 式(i)的化合物可經由口服或非經胃腸道投與且可被-38- 200838508 Dependence (304.60), inhalation abuse (3〇5 (靡), inhalation poisoning sputum, inhalation, hair) 22, inhalation-induced psychosis, inhalation, swabbing dementia, (292 9). Diseases related to the disease 30" '3, for example, nicotine dependence (.), nicotine withdrawal (292.0), and unrecognized nicotine-related disease (292.9); · Related diseases, such as bird sex (, sputum abuse (305.50), opium poisoning 15 20 ' 鹌 中 poisoning reading 捣 捣 捣 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发 诱发Sexual incompetence, bracts _ induced sleep disorders 'C and confirmed opium _ related diseases Ο%. $; phencyclidine (or phencyclidine) · related diseases, for example, phencyclidine Dependence (=.60), abuse of phencyclidine (10), phencyclidine poisoning (292), phencyclidine poisoning, stupid _ induced psychosis, phencyclidine _ induced emotion Disturbing, phencyclidine-induced anxiety and unconfirmed phencyclidine-related diseases (292.9); sedatives _, sleeping pills _ Or anti-anxiety-related diseases, for example, sedatives, hypnotics, or anxiolytic-dependent (304.10) 'sedatives, hypnotics, or anxiolytics abuse 〇〇5·4〇), sedatives, sleeping pills, or anxiolytics Poisoning (Μ2.89), sedatives, hypnotics, or anxiolytics withdrawal (292 〇), sedatives, hypnotics, or anti-anxiety agents, sedatives, sleeping pills, or anti-anxiety agents, sedatives, Sleeping pills _, or anti-anxiety agents _ persistent dementia, sedatives -, sleeping pills -, or anti-anxiety agents - persistent amnesia 'sedatives _, female sleep music -, or anti-anxiety agents - induced psychosis, sedatives _, sleeping pills _, -39- 200838508 or anti-anxiety-induced emotional distress, sedative-, sleeping pills-, or anti-anxiety-induced anxiety, sedatives, hypnotics, or anti-anxiety-induced sexual incompetence, sedatives -, Sleeping pills - or anti-anxiety - induced sleep disorders and unconfirmed sedatives -, hypnotics - or anti-anxiety 5 - related diseases (292.9); multiple drug-related diseases, for example, multiple drugs Dependence (304.80); and other (or unknown) drug-related diseases, such as anabolic steroids, nitrate inhalers, and nitrous oxide; sleep disorders include primary sleep disorders, for example, abnormal sleep 40, for example, primary insomnia (307., 42), primary narcolepsy (307.44), narcolepsy (347), respiratory-related sleep disorders (780.59), circadian rhythm and sleep disorders (307.45) ) and unrecognized sleep abnormalities and related diseases (307.47); primary sleep disorders such as nightmares (307.47), sleep panic disorder (307.46), sleepwalking (307.46), and unidentified dormancy 15 Disease-related diseases (307.47); sleep disorders associated with other mental illnesses, such as insomnia associated with other mental illnesses (307.42) and narcolepsy associated with other mental illnesses (307.44); sleep caused by physical illness Diseases; and substance-induced sleep disorders, including subtypes: type of insomnia, type of sleepiness, type of parasomnia, and mixed types; 2 〇 abnormal diet, for example, anorexia (307.1) includes the following subtypes: fasted and mad/clear; bulimia (307.51) includes subtypes: clearance and non-clearing; obesity · compulsive eating disorders; mad eating; Confirmed diet abnormalities - related diseases (307.50); Sexual dysfunction including sexual desire disorders, for example, low libido disorders -40-200838508 (302.71), and sexual aversion (302.79); sexual excitement, for example, female cold Sense (302.72) and male erectile dysfunction (3〇2·72); orgasm disorders, for example, female orgasm disorders (3〇2.77); male orgasm disorders (3〇2.74) and premature ejaculation (302.75); sexual pain disorder, For example, painful intercourse (3〇2·76) 5 and vaginal fistula (306.51); other unrecognized sexual dysfunction (3〇2·70); sexual abnormal behavior, for example, dew yin (3〇 2·4), Fetish (302.81), 挨 癖 (302.89), pedophilia (302.2), masochism (302.83), sexual Lu (302.84), dissident fetish (3〇2· 3), voyeurism (302.82) and other unrecognized sexual anomalies (3〇2 9); gender 10 identity disorders, for example, children Do not recognize the condition (302.6) and adolescent or adult gender identity disorder (302.85); and other unrecognized libido disorders (302.9); in another embodiment of the invention, a compound of formula (1), or a pharmaceutically acceptable thereof, is provided A salt or solvate used to prepare a medical product for the treatment of madness. In another embodiment of the invention, a method of treating a genus of rabies comprising administering to the subject an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, is provided. In another embodiment of the invention, there is provided a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for the treatment of obesity. In another embodiment of the invention, there is provided a method of treating lactation with obesity, comprising administering to the subject an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvent thereof. Compound. 200838508 Compounds of formula (i) may be administered orally or parenterally and may be administered
配製成適於供投與的型式以提供藥劑供治療相關於NPY 之各種疾病,包括,例如,心血管疾病類(例如,高血壓、 腎病、心臟病、a管痙攣、a管硬化)、中樞神經系統疾 5 病類(例如,飢餓、憂鬱、焦慮、發作、癲癇、癡呆、痛 苦、酗酒、藥物戒斷)、代謝性疾病類(例如,肥胖、糖尿 病、激素異常、高膽固醇症、高脂血症)、性及生殖功能 _ 異常、胃-腸蠕動性疾病、呼吸異常、炎症或青光眼等等, 較佳地為用於治療飢餓症、肥胖、糖尿病等等。 10 雖然在療法上,具治療地有效量之式(I)化合物,或其 一種藥學上可接受的鹽或溶劑化物,可以呈原化合物被使 用但#乂佳地係作為一種活性成分被配製成一種藥學的組 成物使用,於是,本發明的另一具體實例係提供一種藥學 15 2組成物,其係包含一種式⑴的化合物,或其一種藥學上 5 ^接受的鹽或溶劑化物,與一或多種藥學上可接受的载劑 • 釋咖、或賦形劑類所形成之混合物,載劑類、稀 制或賦形劑類必須為可被接受的,係指彼等需與配 『月之其他成分為相容且無害於使用者的物質;本發 20 Z的f —具體實例也提供製備-種藥學組成物之方法,包 兩ιΓί合式⑴的化合物,或其一種藥學上可接受的鹽或溶 ,.. /、或多種樂學上可接受的載劑類、稀釋劑類、 或賦形劑類。 盥本I明的樂學組成物可被配製供任一適當的途徑投 人例如,經由口服(包括頰内或舌下)、直腸、鼻内、局 -42- 200838508 部的(包括頰内、舌下或經皮膚的)、陰道内的或非經胃腸 道的(包括皮下的、肌肉内的、靜脈内的或經皮膚的)路徑, 於是,本發明的組成物可被配製成,例如,錠片、膠囊、 粉劑、粒劑、錠劑、乳霜或液體製劑類,例如,口服或無 5 菌的非經胃腸施用之溶液或懸浮液劑類,這樣的藥學的配 製劑類可利用製藥學中已知的任意方法製備,例如,將活 性成分與載劑(們)或賦形劑(們)結合在一起。 供口服投與之錠劑及膠囊劑可呈單位劑量型式,且可 I 能含有傳統的賦形劑,例如,钻結劑,例如,濃漿、阿拉 -10 伯膠、明膠、山梨糖醇、特拉加康斯樹膠、或聚乙烯吼咯 酮;填料類,例如,乳糖、糖、玉米-澱粉、磷酸鈣、山梨 糖醇或甘胺酸;錠片潤滑劑類,例如,硬脂酸鎂、滑石、 聚乙二醇或二氧化矽;崩散劑類,例如,馬鈴薯澱粉;或 可接受的潤濕劑,例如月桂基硫酸鈉,錠劑可根據一般藥 15 學實作中已知的方法被塗裝;口服液體製劑類之型式可 為,例如,水性或油性懸浮液、溶液、乳液、濃漿液或驰 * 劑;或可呈現為一種乾燥產物,再於使用前,與水或適當 的媒質重組成液態製劑使用,這樣的液體製劑可含有傳統 的添加物,例如,懸浮劑類,例如,山梨糖醇、曱基纖維 20 素、葡萄糖漿、動物膠、羥乙基纖維素、羧曱基纖維素、 硬脂酸鋁凝膠或氫化的食用脂類、乳化劑類,例如,卵磷 脂、單油酸山梨醇酐酯、或阿拉伯樹膠;非水性的媒質類 (包括食用油類),例如,杏仁油、油基S旨類,例如甘油、 丙二醇、或乙醇;防腐劑類,例如,對-羥基苯曱酸之甲基 -43- C S ) 200838508 或丙基酯或山梨酸,以及,有必要的話,傳統的風味劑或 著色劑類。 本發明的局部用配製劑類可呈現為,例如,油膏、乳 霜或化妝水、眼膏及眼或耳滴劑、浸潤的敷料及氣溶液 5 類,且可含有適當的傳統的添加物類,例如,防腐劑類、 溶劑類以幫助藥物之滲透以及在油膏及乳霜内之潤膚劑 類,配製劑也含有相容之傳統的載劑類,例如,乳霜或油 膏基質及用於化妝水之乙醇或油基醇,這類載劑可以約 1%至約98%的量存在於配製劑内,更通常地,它們的含 ίο 量可達約配製劑之80%。 適於供非經胃腸道投與之藥學的配製劑包括水性及 非水性的無菌注射溶液,其中可含有抗氧化劑類、缓衝 劑、制菌劑及用於使配製劑呈現為與接受者的血液為等滲 性之溶質類;以及水性及非水性的無菌懸浮液,其中可含 15 有懸浮劑及增稠劑,此配製劑可放置於單位-劑量或多重- 劑量容器内,例如,密封的安瓶瓶或小玻璃瓶内,且可被 ^ 儲存於一種冷象乾燥的狀態,使用前僅需添加無菌的液體 載劑,例如供注射用的水,即可被使用;臨時的注射溶液 及懸浮液也可由無菌的粉劑、粒劑及錠劑製備。 20 適於供直腸施用之藥學的配方可呈栓劑或灌腸劑被 投與。 適於供鼻内施用之藥學的配方,其中載劑為一種固體 者可能包括粒子大小為,例如,20至500微米,以使勁方 式吸入之粗粉劑,即,將鼻子湊近含有粉劑之容器,藉由 -44- 200838508 鼻通迢快輕人之方式,其巾之鋪為 劑,可作為-種鼻喷劑或作成鼻滴劑被使用,=== 分之水性或錄活性成分。 t括活技成 霧ί::共ΓΓΓ與之藥學的配方包括微細粒子塵或 霧器;二:的計量的、劑量加壓的氣溶液、喷 生棉f欠於=道投與之藥學的配方可呈現為陰道藥栓、衛 棉K葙、凝膠、_、泡沫或喷劑之配 Λ0 15 20 配製=:心 成分。 傾-中吊用於适類型配製劑中之其他 可、被:其:有用於治療代謝的及/或 中於不同的時間下分二程 樣的同時的或不同的治療法===有這 可理解的,有用於供治療代謝性及、 任:有Γ二物4其他藥劑的組合之範圍’原則上包括歲 任何組合:療代謝性及/或飲食異常之藥學組成物^ 之具其—種藥學上可接受的鹽或溶劑化物 人類或見許多因素而定’包括,例如, 嚴重性、年、、、己、體重、需治療的精確性及苴 嚴重ί·生、配製_本質、投與路徑,且最終將由參與的 -45- 200838508 醫生或獸醫生判定;然而,用於供治療ΝΡΎΥ5受體媒介 的疾病之式⑴化合物之有效量,通常每天的用量,對於 使用者(哺乳動物),每公斤體重為使用0.1至100毫克的 量且更常使用1至10毫克的量,於是,就70公斤的成 5 人,每天真正的用量將為自70至700毫克,且這樣的量 可每天以單次或通常為將總量分成多次(例如,二、三、 四、五或六次)劑量使用,其藥學上可接受的鹽或溶劑化 物之有效的量可根據各自式⑴化合物為有效量之比例計 •算而定。 .10 供使用於本發明之式⑴化合物,或其藥學上可接受的 鹽或溶劑化物,可被併用一或多種的其他治療劑,本發明 因此也提供另種具體實施例之一種組合,係包含一種式(I) 之化合物,或其藥學上可接受的鹽或溶劑化物,加上另一 種治療劑,其可為,例如,另種的抗-肥胖劑;本發明的另 15 一具體實施例也提供一種組合物之用途,係包含一種式(I) 之化合物,或其藥學上可接受的鹽或溶劑化物,加上另一 • 種治療劑,用於治療受NPYY5受體媒介之疾病。 當一種式⑴之化合物,或其藥學上可接受的鹽或溶劑 化物,被併用一或多種其他治療劑時,這些化合物可被相 20 繼地或同時地藉由任何方便的路徑投與。 上述之組合物可方便地在藥學的配製劑中以供使用 的形式呈現,且因此藥學的配製劑包含如上述之一種組合 與藥學上可接受的載劑或賦形劑而為本發明之另一具體 實施例,這樣的組合中之個別的組分可被相繼地或同時地 -46- 200838508 在分開的或組合的藥學的配製劑中被投與。 5Formulated in a form suitable for administration to provide a medicament for the treatment of various diseases associated with NPY, including, for example, cardiovascular diseases (eg, hypertension, kidney disease, heart disease, a tube fistula, a tube hardening), Central nervous system disease 5 diseases (eg, hunger, depression, anxiety, seizures, epilepsy, dementia, pain, alcoholism, drug withdrawal), metabolic diseases (eg, obesity, diabetes, hormonal abnormalities, hypercholesterolemia, high Lipidemia), sexual and reproductive function _ abnormal, stomach-intestinal motility disease, respiratory abnormality, inflammation or glaucoma, etc., preferably for treating hunger, obesity, diabetes and the like. 10 Although therapeutically effective, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, may be formulated as the original compound but may be formulated as an active ingredient. In a pharmaceutical composition, a further embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, and One or more pharmaceutically acceptable carriers • a mixture of coffee, or excipients, carriers, excipients or excipients must be acceptable, meaning they are compatible with Other components of the month are compatible and harmless to the user; the present invention provides a method for preparing a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable compound thereof. Salt or dissolved, .. /, or a variety of acceptable carriers, diluents, or excipients. The music composition of the present invention may be formulated for administration by any suitable route, for example, via oral (including buccal or sublingual), rectal, intranasal, intravesical (including buccal, Sublingual or transdermal, intravaginal or parenteral (including subcutaneous, intramuscular, intravenous or transdermal) routes, and thus, the compositions of the present invention can be formulated, for example , tablets, capsules, powders, granules, lozenges, creams or liquid preparations, for example, oral or non-bacterial solutions or suspensions for parenteral administration, such pharmaceutical formulations are available Any method known in the art of pharmacy is prepared, for example, by combining the active ingredient with a carrier or excipient. Tablets and capsules for oral administration can be presented in unit dosage form, and can contain conventional excipients such as, for example, thickening agents, aloe- 10 gum, gelatin, sorbitol, Tragacons gum, or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn-starch, calcium phosphate, sorbitol or glycine; tablet lubricants, for example, magnesium stearate , talc, polyethylene glycol or cerium oxide; disintegrating agents, for example, potato starch; or acceptable wetting agents, such as sodium lauryl sulfate, tablets can be used according to methods known in the general practice 15 Being applied; the oral liquid preparation may be, for example, an aqueous or oily suspension, a solution, an emulsion, a thick slurry or a chiral agent; or may be presented as a dry product, before use, with water or a suitable The medium is reconstituted into a liquid preparation, and such a liquid preparation may contain a conventional additive such as a suspending agent such as sorbitol, sulfhydryl fiber 20, glucose syrup, animal glue, hydroxyethyl cellulose, carboxy hydrazine. Cellulose, hard fat Aluminum gel or hydrogenated edible fats, emulsifiers, for example, lecithin, sorbitan monooleate, or gum arabic; non-aqueous media (including edible oils), for example, almond oil, oil based For the purpose of, for example, glycerin, propylene glycol, or ethanol; preservatives, for example, p-hydroxybenzoic acid methyl-43-CS) 200838508 or propyl ester or sorbic acid, and, if necessary, traditional flavor Agent or colorant. The topical formulations of the present invention may be presented, for example, as ointments, creams or lotions, eye ointments and eye or ear drops, infiltrated dressings and gas solutions, and may contain suitable conventional additives. Classes, for example, preservatives, solvents to aid penetration of the drug, and emollients in ointments and creams, the formulations also contain compatible conventional carriers, for example, cream or ointment bases And ethanol or oleyl alcohol for use in lotions, such carriers may be present in the formulation in an amount from about 1% to about 98%, more typically, they may be present in an amount up to about 80% of the formulation. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostats, and compositions for the formulation The blood is an isotonic solute; and an aqueous and non-aqueous sterile suspension, which may contain 15 suspending and thickening agents, which may be placed in a unit-dose or multi-dose container, for example, sealed In an ampoule or vial, and can be stored in a cold-dried state, only need to add a sterile liquid carrier, such as water for injection, before use; temporary injection solution The suspensions may also be prepared from sterile powders, granules and lozenges. 20 Formulations suitable for rectal administration may be administered as a suppository or enemas. A formulation suitable for intranasal administration wherein the carrier is a solid which may include a coarse powder having a particle size of, for example, 20 to 500 microns, which is inhaled in a vigorous manner, i.e., bringing the nose close to the container containing the powder, From -44- 200838508 The method of nasal sputum is quick and light, and the towel is used as a nasal spray or as a nasal drop, === water or active ingredient.括 活 活 ί ί ί :: ΓΓΓ ΓΓΓ ΓΓΓ 药学 ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί ί The formula can be formulated as a vaginal suppository, a velvet sponge, a gel, a _, a foam or a spray. 0 15 20 Formulation =: Heart component. Pour-and-hanger for other types of formulations in a suitable type: it: there are simultaneous or different treatments for the treatment of metabolism and/or for two-way treatment at different times === have this It is to be understood that there is a range of combinations for the treatment of metabolic properties and any other agents of the present invention. In principle, any combination of ages: a pharmaceutical composition for treating metabolic and/or abnormal diets - A pharmaceutically acceptable salt or solvate is determined by humans or by a number of factors including, for example, severity, year, age, weight, need for treatment accuracy, and sputum severity, preparation, nature, and investment. And the path, and will ultimately be judged by the participating doctor or veterinarian; however, the effective amount of the compound of formula (1) for the treatment of the ΝΡΎΥ5 receptor vector, usually daily, for the user (mammal) , the amount of 0.1 to 100 mg per kilogram of body weight and more often used 1 to 10 mg, so the actual amount of 70 kg for 5 people per day will be from 70 to 700 mg, and the amount can be Single or pass every day To divide the total amount into multiple (eg, two, three, four, five or six) doses, the effective amount of the pharmaceutically acceptable salt or solvate thereof may be based on the ratio of the compound of formula (1) to the effective amount. • It depends. .10 A compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, for use in the present invention may be used in combination with one or more other therapeutic agents, and the invention thus also provides a combination of other specific embodiments. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in addition to another therapeutic agent, which may be, for example, another anti-obesity agent; another embodiment of the invention The invention also provides a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in addition to another therapeutic agent for the treatment of a disease mediated by the NPYY5 receptor . When a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, is used in combination with one or more other therapeutic agents, these compounds can be administered sequentially or simultaneously by any convenient route. The above compositions may conveniently be presented in a pharmaceutical formulation for use, and thus the pharmaceutical formulation comprises a combination of the above and a pharmaceutically acceptable carrier or excipient which is a further In a particular embodiment, the individual components of such combinations can be administered sequentially or simultaneously -46-200838508 in separate or combined pharmaceutical formulations. 5
-10 當在相同的配方中併用時,可理解的,兩化合物彼此 應為穩定且相容的,且與配方中之其他組分也為相容而被 配製成可供投與型式,當彼等被分開地配製時,它們可以 任何方便的配製劑被提供,如同本技藝中所知提供這類化 合物之方式。 當使用一種化合物而併用第2種治療相同疾病之治療 活性劑時,各化合物之劑量將與單獨使用各化合物之劑量 不同,適當的劑量可由本技藝的行家輕易地判定。 下述實例描述在實驗室合成本發明之特定的化合物 且決非以任何方式限制本發明的範圍僅為這些化合物及 或方法,可理解的,雖然其中使用了特定的試劑、溶劑、 溫度及時間歷程,仍有可能有許多相當的方法可被使用以 產生類似的結果,本發明意欲包含這類相當物。 15-10 When used in combination in the same formulation, it is understood that the two compounds should be stable and compatible with each other and compatible with the other components of the formulation to be formulated for administration. When they are formulated separately, they can be provided in any convenient formulation, as is known in the art to provide such compounds. When a compound is used and a therapeutically effective agent for the same disease is treated with the second, the dose of each compound will be different from the dose of each compound alone, and the appropriate dose can be easily determined by the expert of the art. The following examples describe the synthesis of specific compounds of the invention in the laboratory and are in no way intended to limit the scope of the invention to only those compounds and or methods, it being understood, although specific reagents, solvents, temperatures and times are used therein. It is still possible that many equivalent methods can be used to produce similar results, and the present invention is intended to encompass such equivalents. 15
20 實驗部分 本發明 以下述化合物進行說明。 縮寫字 DMAP 4-二甲基胺基吡啶 DIPEA N,N-二異丙基乙基胺 TEA 三乙基胺 TFA 三氟乙酸 EtOAc 乙酸乙酯 EDC.HC1 N-(3-二曱基胺基丙基)-Nf-乙基碳二醯胺鹽酸 -47- 200838508 H0Bt.H20 1-經基苯甲基三嗤水合物 DMSO 二甲亞礙 DCM 二氯曱烷 DMF N,N-二甲基曱醯胺 HATU (0-7-氮雜苯并三唑小基)-N,N,N’,N’·四曱基鐳 六氟磷酸酯) THF 四氫吱喃 MDAP 質量導向的自動純化 4〇 化合物的命名使用ACD/Name PRO 6·02化學命名軟 體(Advanced Chemistry Development Inc·,Toronto, Ontario, M5H2L3, Canada)其中立體化學的標示符號(5r,8r)及(5s,8s) 分別以更廣泛被使用之「反式」及「順式」標示符號取代。 15 分析的設備 氫質子磁振(Proton Magnetic Resonance,NMR)頻譜係 鲁 於Varian儀器,在300、400、500或600 MHz下,或於 Bruker儀器,在300或400 MHz下之記錄,化學位移 (Chemical shifts)的單位為ppm (δ),使用殘留的溶劑線作 2〇 為内部的標準,分裂的圖譜被標示成:s,單峰;d,雙峰· f 三峰;q,四重峰;m,多重峰;b,廣闊的;NMR光譜在25 至90°C的溫度範圍間被記錄,當有多於一個的順式構象 (conformer)被偵測到時,以佔最多量的化學位移被記錄。 質譜(MS)取自一種4 II三段四極柱串聯式質譜儀(4 π -48 - 200838508 triple quadrupole Mass Spectrometer, Micromass UK)或一 種Agilent MSD 1100質譜儀,以£8(+)及£8(-)離子化模 式操作,並指明係採用這種方法。 HPLC-質譜(HPLC-MS)係使用一種 Agilent LC/MSD 5 1100質譜儀,在ES(+)及ES㈠離子化模式偶合HPLC儀 器 Agilent 1100 Series [LC/MS-ES (+)下操作:分析進行於 一種 Supelcosil ABZ+Plus (33x4.6 毫米,3 米)(移動相: _ 100% [水+0·1〇/〇 曱酸],1 分鐘,再自 1〇〇〇/0 [水+01〇/〇 甲酸]20 Experimental part The present invention is illustrated by the following compounds. Abbreviation DMAP 4-dimethylaminopyridine DIPEA N,N-diisopropylethylamine TEA Triethylamine TFA Trifluoroacetic acid EtOAc EDC.HC1 N-(3-didecylaminopropyl ))-Nf-ethylcarbodiamine hydrochloride-47- 200838508 H0Bt.H20 1-Phenylbenzyltrifluoride DMSO Dimethyl sulphate DCM Dichlorodecane DMF N,N-dimethylhydrazine Amine HATU (0-7-azabenzotriazole small group)-N,N,N',N'·tetradecyl radium hexafluorophosphate) THF tetrahydrofuran MDAP mass-directed automatic purification of 4〇 compound The naming uses ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada) where the stereochemical notation (5r, 8r) and (5s, 8s) are more widely Replace with the "trans" and "cis" signs. 15 Analytical equipment The Proton Magnetic Resonance (NMR) spectrum is recorded on a Varian instrument at 300, 400, 500 or 600 MHz, or on a Bruker instrument, recorded at 300 or 400 MHz, chemical shift ( The unit of Chemical shifts) is ppm (δ), and the residual solvent line is used as the internal standard. The split spectrum is labeled as: s, single peak; d, double peak · f three peaks; q, quartet; m, multiple peaks; b, broad; NMR spectra are recorded over a temperature range of 25 to 90 ° C. When more than one cis conformer is detected, the most common chemical shift is taken. is recorded. Mass spectrometry (MS) was taken from a 4 II three-stage quadrupole tandem mass spectrometer (4 π -48 - 200838508 triple quadrupole Mass Spectrometer, Micromass UK) or an Agilent MSD 1100 mass spectrometer at £8 (+) and £8 ( -) Ionization mode operation and indicate that this method is used. HPLC-MS was performed on an Agilent LC/MSD 5 1100 mass spectrometer using an ES (+) and ES (I) ionization mode coupled HPLC instrument Agilent 1100 Series [LC/MS-ES (+): analysis performed For a Supelcosil ABZ+Plus (33x4.6 mm, 3 m) (mobile phase: _ 100% [water + 0·1 〇 / citric acid], 1 minute, then from 1 〇〇〇 / 0 [water + 01 〇/〇carboxylic acid]
至5% [水+0.1%曱酸]及95%[乙腈],5分鐘内,最後在這些 0 條件下經2分鐘;T=40°C;流速=1毫升/分鐘;LC/MS-ES ㈠:分析進行於一種 Supelcosil ΑΒΖ+Phis (33χ4·6 毫米,3 米)(移動相:100% [水+〇·〇5%氨水],1分鐘,再自ι〇0% [水 +0.05%氨水;]至5% [水+0.05%氨水]及95%[乙腈],5分鐘 内’最後在這些條件下經2分鐘;T=40°C;流速二1毫升/ 5 分鐘),在質譜中,分子離子叢集中僅報導一個頂峰,於 描述化合物之分析的特性中,以”HpLC_MSi”指明係採用 這種方法。 或者,HPLC-MS測量係使用一種piatfornl LCZTM單 段四極桎質譜儀,與一種HPLC系統Agilent 1100 Series ί〇 偶合的儀器上進行,實驗的條件為:管柱XBridge C18,(5To 5% [water + 0.1% citric acid] and 95% [acetonitrile], within 5 minutes, finally under these conditions for 2 minutes; T = 40 ° C; flow rate = 1 ml / min; LC / MS-ES (a): The analysis was carried out on a Supelcosil ΑΒΖ+Phis (33χ4·6 mm, 3 m) (mobile phase: 100% [water + 〇·〇 5% ammonia], 1 minute, then from ι〇0% [water + 0.05% Ammonia;] to 5% [water + 0.05% ammonia water] and 95% [acetonitrile], within 5 minutes 'finally under these conditions for 2 minutes; T = 40 ° C; flow rate 2 1 ml / 5 minutes), in mass spectrometry In the molecular ion cluster, only one peak is reported. In the characteristics describing the analysis of the compound, "HpLC_MSi" indicates that this method is employed. Alternatively, the HPLC-MS measurement was performed on an instrument coupled to an HPLC system Agilent 1100 Series 使用 using a piatfornl LCZTM single-stage quadrupole mass spectrometer with the following conditions: column XBridge C18, (5)
笔米4·6 X 50毫米),管柱溫度30°C,移動相,A=水 +〇·1%ΤΡΑ 及 B=MeCN,梯度,t=0 分鐘 0% (B)至 60% (B),15分鐘内至95〇/〇 (B),3.5分鐘内,持續1·5分鐘(t=6.60 分鐘〇%B停止時間=7·0分鐘),流速:2毫升/分鐘,DAD 49- 200838508 UV範圍210至350 nm,MS離子化模式,正電麗(es+), MS範圍110至1100原子量單位,,於所述化合物之分析 特性中,以”HPLC-MS 2”指明係採用這種方法。 結合於頂學之總離子流(TIC)及DAD UV色譜微量物 5 (chromatographic traces)與 MS 及 UV 光譜也於一種配備 2996 PDA偵測器之UPLC/MS AcquityTM系統上並偶合於 一種Waters Micromass ZQTM質譜,於正或負電灑離子化 鲁 模式下進行測定[LC/MS-ES (+/-):分析的進行使用一種 AcquityTM UPLC BEH C18 管柱(50 X 21 毫米,7 微米粒 10 子大小),管柱溫度40°C(移動相:A-水+0.1%曱酸/B-乙腈 +0.075%曱酸,流速:1.0毫升/分鐘,梯度:户0分鐘3〇/以, t=0.05 分鐘 6% B ’ t=0.57 分鐘 70% B,ί=1·4 分鐘 99% Β,t=1.45分鐘3%Β)],於所述化合物之分析特性中,以 nUPLC-MSn指明係使用這種方法測定。 15 當反應用及微波照射時,係使用一種Pers〇nalPen meter 4·6 X 50 mm), column temperature 30 ° C, mobile phase, A = water + 〇 · 1% ΤΡΑ and B = MeCN, gradient, t = 0 min 0% (B) to 60% (B ), within 15 minutes to 95 〇 / 〇 (B), within 3.5 minutes, lasting 1-5 minutes (t = 6.60 minutes 〇 % B stop time = 7.5 minutes), flow rate: 2 ml / min, DAD 49- 200838508 UV range 210 to 350 nm, MS ionization mode, positive electricity (es+), MS range 110 to 1100 atomic weight units, in the analytical properties of the compound, indicated by "HPLC-MS 2" method. Total ion current (TIC) and DAD UV chromatographic traces combined with MS and UV spectra were also coupled to a UPLC/MS AcquityTM system equipped with a 2996 PDA detector and coupled to a Waters Micromass ZQTM Mass spectrometry, measured in positive or negative ionization ionization mode [LC/MS-ES (+/-): analysis was performed using an AcquityTM UPLC BEH C18 column (50 X 21 mm, 7 micron 10 sub-size) , column temperature 40 ° C (mobile phase: A-water + 0.1% citric acid / B-acetonitrile + 0.075% citric acid, flow rate: 1.0 ml / min, gradient: household 0 minutes 3 〇 /, t = 0.05 minutes 6% B ' t = 0.57 minutes 70% B, ί = 1 · 4 minutes 99% Β, t = 1.45 minutes 3% Β)], in the analysis characteristics of the compound, the use of nUPLC-MSn indicates that the system uses Method determination. 15 When using the reaction and microwave irradiation, use a Pers〇nal
Chemistry EmrysTM Optimizer 之設備。Equipment for Chemistry EmrysTM Optimizer.
鲁 快速矽膠層析法係在矽膠230-400篩目(由Merck AGLu Rapid Gel Chromatography is available in Silicone 230-400 mesh (by Merck AG
Darmstadt,Germany 供應)或於 Varian Mega Be_Si 預充填 的筒形物或預充填的Biotage石夕膠筒上進行。 20 SPE-SCX筒為由Varian供應之離子交換固相萃取 筒,與SPE-SCX筒一起使用的溶離液為曱醇,接著使用 在曱醇内之氨水溶液。 在許多的製備法中,純化作用之進行係使用Bi〇tage 手動快速層析法(閃+)或自動快速層析法(水平線)系統,所 -50- 200838508 有這些作業係使用標準的Biotage矽膠筒進行。 SPE-Si筒係由Varian供應的石夕膠固相萃取管柱。 5Available from Darmstadt, Germany) on Varian Mega Be_Si pre-filled cartridges or pre-filled Biotage. The 20 SPE-SCX cartridge is an ion exchange solid phase extraction cartridge supplied by Varian. The dissolution solution used with the SPE-SCX cartridge is decyl alcohol followed by an aqueous ammonia solution in sterol. In many preparations, purification is carried out using Bi〇tage manual flash chromatography (flash +) or automated flash chromatography (horizontal line) systems, which are used in these operations using standard Biotage silicones. The tube is carried out. The SPE-Si cylinder is a Shishi gum solid phase extraction column supplied by Varian. 5
-10 15-10 15
20 許多的製備法中,純化作用係於配備Waters 2996 PDA 偵測器及偶合ZQ™質譜儀(Waters)之一種質量-指向的自 動純化(Mass-Directed Autopurification,MDAP)系統 Fractionlynx™,在正及負電灑模式ES+、ES_下操作(質量 範圍100-1000),使用一套酸性以及鹼性半-製備性梯度: 方法A:層析酸性條件用於至多達30毫克的粗製品: 管柱:1〇〇χ21·2 毫米 SupelcosilTMABZ+Plus (5 微米粒 子大小) 移動相:A[水+0.1%曱酸]/B[乙腈+〇·ι%甲酸] 流速: 20毫升/分鐘 梯度:5% B,經1分鐘,95% B,在9分鐘内,100% B, 在3.5分鐘内 方法B:層析酸性條件用於至多達1〇〇毫克的粗製品: 言柱:150x30毫米XTerraPrepMS C18 (10微米粒子大 小) 移動相:A[水+〇·1%甲酸]/b[乙腈+〇·ι〇/0曱酸] 流速: 40毫升/分鐘 梯度:1%Β至1〇〇% Β,在7分鐘内,持續7·5分鐘。 方法C:層析鹼性條件用於至多達毫克的粗製品: -51- 200838508 管柱: 150x30毫米XTerraPrepMS C18 (10微米粒子大 小) 移動相:A·水+ l〇mM碳酸銨(以氨水調整至pH 1〇)/β·乙 腈 流速:40毫升/分鐘 梯度:10% Β,經0.5分鐘,95%Β,在12.5分鐘内。 所有的反應均以薄層層析法監測,於0.25毫米Ε. Merck矽膠板(60F-254)上,以UV光、碘、5%乙醇性磷鉬 酸、水合茚三酮溶液或香草素溶液檢視。 支捋性化i物及中間物 中間物1_20 In many preparations, the purification is based on a Mass-Directed Autopurification (MDAP) system FractionlynxTM equipped with a Waters 2996 PDA detector and a coupled ZQTM mass spectrometer (Waters). Negative spray mode ES+, ES_ operation (mass range 100-1000), using a set of acidic and basic semi-preparative gradients: Method A: Chromatographic acid conditions for up to 30 mg of crude product: Column: 1〇〇χ21·2 mm SupelcosilTM ABZ+Plus (5 micron particle size) Mobile phase: A[water + 0.1% citric acid]/B [acetonitrile + 〇·ι% formic acid] Flow rate: 20 ml/min Gradient: 5% B , after 1 minute, 95% B, within 9 minutes, 100% B, within 3.5 minutes Method B: Chromatographic acid conditions for up to 1 mg of crude product: Column: 150 x 30 mm XTerraPrepMS C18 (10 Micron particle size) Mobile phase: A[water + 〇 · 1% formic acid] / b [acetonitrile + 〇 · ι〇 / 0 decanoic acid] Flow rate: 40 ml / min Gradient: 1% Β to 1 〇〇 % Β, in Within 7 minutes, lasting 7.5 minutes. Method C: Chromatographic alkaline conditions for up to milligrams of crude product: -51- 200838508 Column: 150 x 30 mm XTerraPrepMS C18 (10 micron particle size) Mobile phase: A·water + l〇mM ammonium carbonate (adjusted with ammonia) To pH 1 〇) / β · acetonitrile flow rate: 40 ml / min Gradient: 10% Β, 0.5 min, 95% Β, within 12.5 minutes. All reactions were monitored by thin layer chromatography on a 0.25 mm Mer. Merck silicone board (60F-254) with UV light, iodine, 5% ethanolic phosphomolybdic acid, ninhydrin solution or vanillin solution. View. Branching i and intermediates 1_
Li則氧氧雜—3-氮雜螺「4.51癸烷-8-羧酸乙酷Li is oxyoxa-3-azaspiro"4.51 decane-8-carboxylic acid ethane cool
舲乙基-4-羥基-4-({苯基[(笨氧基)羰基]胺基}曱基)_ 己烧舰S旨(中間物2) (127.3毫克,Q 32G毫莫耳)溶解於 水曱苯(2毫升)後,擾拌中,加入氮化納(6〇% Μ身 在室溫下攪拌過夜,將混合物倒入水中 ,·毛兄 ^ y,以EtOAc萃] 有機層以Na2S04乾燥,過淚,直空下⑽ ‘具工下,辰縮,製得粗製 -52- 20 200838508 側氧-3-苯基-氧雜_3_氮雜螺[4·5]癸烷-8-羧酸乙酯(93.2 毫克),未再精製下被使用;MS,m/z: 304 [M+Hf。 使用類似方法製備得的另批樣品具有如下之NMR光 譜:4 NMR (400 MHz,CDC13): δ 1.23-1.33 (m,3H) 1.55-1.69 (m,2H) 1.86-2.21 (m,6H) 2.32-2.41 (m,1H) 3·71_3·74 (m,2H) 4.11-4.22 (m,2H) 7.11-7.18 (m,1H) 7·35-7·43 (m,2H) 7.50-7.59 (m5 2H),順式/反式 70:30 中間 『(苯氧基)羰基1胺基}甲基)環己烷羧酸ι II.Ethyl 4-hydroxy-4-({phenyl[(indoloxy)carbonyl]amino}indenyl)_ 己烧船S (Intermediate 2) (127.3 mg, Q 32G millimolar) dissolved After hydrazine benzene (2 ml), the mixture was stirred, and sodium nitride was added (6 〇% was stirred at room temperature overnight, and the mixture was poured into water, and the mixture was extracted with EtOAc). Na2S04 is dry, tears, under the air (10) 'has the work, the shrink, the crude is made -52-20 203838 Ethyl 8-carboxylate (93.2 mg) was used without re-purification; MS, m/z: 304 [M+Hf. </ RTI> </ RTI> , CDC13): δ 1.23-1.33 (m, 3H) 1.55-1.69 (m, 2H) 1.86-2.21 (m, 6H) 2.32-2.41 (m, 1H) 3·71_3·74 (m, 2H) 4.11-4.22 (m,2H) 7.11-7.18 (m,1H) 7·35-7·43 (m,2H) 7.50-7.59 (m5 2H), cis/trans 70:30 intermediate "(phenoxy)carbonyl 1 Amino}methyl)cyclohexanecarboxylic acid ι II.
,在o°c下,對攪拌中、溶解於DCM(10毫升)之粗製 4-經基^4-[(笨基胺基)_甲基]環己烷羧酸乙酯(中間物3) (3·=耄莫耳)之溶液,加入DIPEA(665微升,3.82毫莫耳) 基氯甲酸g旨(48〇微升,3·82毫莫耳),在室溫下將反應 、,一物授拌過仗’將混合物倒入一種飽和的水溶液 =以DCM萃取;有機層以Na2S04乾燥,過濾,真空下濃 =,粗製品藉由矽膠層析法純化,以環己烷:Et〇Ac溶離, 製知標題化合物(12?.3毫克,8%); (Rf=0.48,環己 -53· 200838508 烷:EtOAc 7:3); MS: m/z 398 [M+H]+,使用一種類似的方 法製備得之另一批相同的化合物具有下述之NMR光譜: Η NMR (400 MHz, CDC13): δ L18-L36 (m? 5Η) 1.47-1.94 (m,7Η) 2·14_2·22 (m,1Η) 2.39-2.46 (m5 1Η) 3·82-3·90 (m, 5 1H) 3.91-3.95 (m,1H) 4·05-4·19 (m,2H) 7.03-7.14 (m,2H) 7.16-7.24 (m,1H) 7·28_7·44 (m,6H),順式/反式 70:30 中間物3, crude 4-(4-phenylamino)-methyl]cyclohexanecarboxylate (Intermediate 3), dissolved in DCM (10 mL). (3·=耄莫耳) solution, add DIPEA (665 μl, 3.82 mmol) chloroformate g (48 μL, 3.82 mmol), react at room temperature, The mixture is poured into a saturated aqueous solution = extracted with DCM; the organic layer is dried over Na2SO4, filtered, and concentrated under vacuum = and the crude product is purified by gelatin chromatography to give hexane: Et 〇 The title compound (12..3 mg, 8%) was obtained eluted with EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: Another batch of the same compound prepared by a similar method has the following NMR spectrum: Η NMR (400 MHz, CDC13): δ L18-L36 (m? 5Η) 1.47-1.94 (m, 7Η) 2·14_2 ·22 (m,1Η) 2.39-2.46 (m5 1Η) 3·82-3·90 (m, 5 1H) 3.91-3.95 (m,1H) 4·05-4·19 (m,2H) 7.03-7.14 (m, 2H) 7.16-7.24 (m, 1H) 7·28_7·44 (m, 6H), cis/trans 70:30 Intermediate 3
_ιο 4-經_基_+『(苯基胺基)曱基撼烷羧酸乙酯_ιο 4-经_基_+ "(Phenylamino) decyl decanecarboxylic acid ethyl ester
將氧雜螺[2.5]辛烧-6-叛酸乙g旨(中間物4方法4a 704.5毫克,3·82宅莫耳)溶解於第三_Bu〇H (4毫升)後,加 15 入苯胺(697微升,7.65毫莫耳,Aldrich),以微波照射,在 150°C下攪拌及加熱30分鐘兩次,將混合物倒入一種飽和 的NHUC1水溶液並以乙酸乙酯萃取;有機層以1^28〇4乾 综,過濾,真空下濃縮,製得粗製的4-經基_4_[(苯基胺基) 曱基]-環己烷羧酸乙酯(1.19克),未再精製下被使用。 20 另一批使用類似方法製備得的樣品具有如下述之 NMR 光譜:4 NMR (400 MHz,CDC13): δ 1·22-1·30 (m,3H) -54- 200838508 1.36-2.02 (m,9H) 2.23-2.34 (m,1H) 2.45-2.54 (m,1H) 3.09-3.13 (m? 1H) 3.16-3.21 (m? 1H) 4.10-4 20 (m 2H) 6·65-6·77 (m,3H) 7.14-7.24 (m,2H),順式/反式 35:65 5 中間物4 1-氣雜螺「2.51辛烷-6-羧酸乙酯Dissolve oxaspiro[2.5]octane-6-rebel acid (intermediate 4 method 4a 704.5 mg, 3.82 house Moule) in the third _Bu〇H (4 ml), add 15 Aniline (697 μL, 7.65 mmol, Aldrich), was irradiated with microwave, stirred and heated at 150 ° C for 30 minutes. The mixture was poured into a saturated aqueous solution of NHUC1 and extracted with ethyl acetate. 1^28〇4 dry hectified, filtered and concentrated under vacuum to give crude 4-(4-(phenylamino)indolyl]-cyclohexanecarboxylic acid ethyl ester (1.19 g). It is used below. 20 Another batch of samples prepared using a similar method has an NMR spectrum as follows: 4 NMR (400 MHz, CDC13): δ 1·22-1·30 (m, 3H) -54- 200838508 1.36-2.02 (m, 9H) 2.23-2.34 (m,1H) 2.45-2.54 (m,1H) 3.09-3.13 (m? 1H) 3.16-3.21 (m? 1H) 4.10-4 20 (m 2H) 6·65-6·77 ( m,3H) 7.14-7.24 (m,2H), cis/trans 35:65 5 intermediate 4 1-gas snail "2.51 octane-6-carboxylic acid ethyl ester
方法4a 將三甲基亞砜鏽碘及第三-丁氧化鉀(如Synthetic Communications,33(12),2135-2143 之報告中方法製備; 3.9克,11.76毫莫耳)的混合物加入至溶解於DMS〇(2〇毫 升)的4_侧氧環己烷羧酸乙酯(1克,5·87毫莫耳,八阶地) 之溶液内,在室溫下將反應混合物攪拌過夜,將混合物倒 入水中並以二乙醚萃取,有機層以乾燥,過濾, 真空下濃縮,製得1-氧雜螺[2·5]辛烷-6-羧酸乙酯(7〇4.5 t克,65%),未再精製下被使用。 另批使用類似方法製備得的相同化合物具有如下 途之 NMR 光譜:4 NMR (400 MHz, CDC13)·· δ 1.20 (t,3H) 1.27-1.49 (m? 2H) 1.63-2.04 (m5 6H) 2.26-2.28 (m? 2.49-2.59 (m,2H)4.〇6 (q,2H)順式/反式 65:35 -55- 200838508 方法 將 2,8 9 二 s 一碳燒(可購Γ 基仏以-異氮雜+碟雙環阳斯 混合物,在〇5’ 14笔升,3.94宅莫耳〕及乙腈(15毫升> 的 3.97毫莫耳’加入至攪拌中的三甲基硫鏽碘(〇.81克, 耳)的_二7,己驗酸乙錄563克,3.31毫莫 至室溫,再攪拌=±C下將混合f擾拌3〇分鐘,再回溫 •10 15 所得懸浮物攪拌3〇 /:減辰鲕’加二乙醚稀釋,將 _,合=二二再·予,過渡’遽餅以更多的乙 口併乙醚層,減屋濃縮,殘留物在si〇2上層析 (B!^25M管柱),以梯度為5%七%之舰c/環己烧 洛離,衣传反式:順式之比例約為6〇:4〇之標題化合物之混 合物,為一種無色油質物(250毫克); iHNMR(4〇〇MHz,CDCl3“;.27(3Hw_,t) 1.37-1.52 (2H 兩異構物,m),1.68-2.14 (6H 兩異構物,m) 2.35-2.48 (m 兩異構物,m),2.62 (2H 同侧異構物,s),2 65 (2H異側異構物,s),4.16 (2H兩異構物,q)。 中間物5 2-侧氣-3-笨基-1-氣雜-3-氮雜螺_ 20Method 4a Add a mixture of trimethylsulfoxide rust iodine and third potassium butoxide (as prepared by the method of Synthetic Communications, 33(12), 2135-2143; 3.9 grams, 11.76 millimoles) to dissolve DMS 〇 (2 〇 ml) of a solution of ethyl 4-oxocyclohexanecarboxylate (1 g, 5·87 mmol, octagonal), the reaction mixture was stirred at room temperature overnight and the mixture was poured The mixture was poured into water and extracted with diethyl ether. The organic layer was dried, filtered, and concentrated in vacuo to give ethyl 1-oxaspiro[2·5]octane-6-carboxylate (7 〇 4.5 t, 65%) It is used without refining. Another batch of the same compound prepared by a similar method has the following NMR spectrum: 4 NMR (400 MHz, CDC13)·· δ 1.20 (t, 3H) 1.27-1.49 (m? 2H) 1.63-2.04 (m5 6H) 2.26 -2.28 (m? 2.49-2.59 (m,2H)4.〇6 (q,2H) cis/trans 65:35 -55- 200838508 Method 2,8 9 2s one carbon burned (purchasable base)仏 - 异 异 异 + 碟 碟 碟 碟 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' (〇.81g, ear) _ 2, 563 grams of acid test, 3.31 millimoles to room temperature, then stir = ± C, mix f fluctuate for 3 , minutes, then return to temperature • 10 15 Stirring the suspension 3 〇 /: minus 鲕 鲕 'diethyl ether diluted, _, combined = two two and then, the transition '遽 cake with more ethyl ether and ether layer, reduced house concentration, residue in si〇 2 on the chromatogram (B!^25M column), with a gradient of 5% and 7% of the ship c/cyclohexanol, and the trans-form: cis ratio is about 6〇: 4〇 of the title compound The mixture was a colorless oily substance (250 mg); iHNMR (4 〇〇 MHz, CDCl3 ";.27 (3Hw_, t) 1.37-1.52 (2H two isomers, m), 1.68-2.14 (6H two isomers, m) 2.35-2.48 (m two isomers, m), 2.62 (2H ipsilateral isomer, s), 2 65 (2H isomer, s), 4.16 (2H isomer, q) Intermediate 5 2-sided gas-3-phenyl-1-pyran-3-azaspiro-20
-56- 3- Φ-、 200838508 將8-(經基甲基)-3-苯基-1-氧雜-3-氮雜螺[4·5]癸烷_2_ 酮(中間物6, 72.5毫克”^了了毫莫耳^在氮氣層内…容解 於乾燥DCM (3毫升)内,分兩批加入Dess_Martin過硤燒 (141.38毫克,0.33毫莫耳,Aldrich),在室溫下使之反應2 小時,將反應物倒入至含有5%Na2S2〇3 (2·5克)之NaHC03 的飽和的溶液中,以DCM萃取,有機層以Na2S〇4乾燥, 真空下濃縮,製得標題化合物,未再精製下被使用。 !H NMR (400 MHz5 CDC13): δ 1.33-2.34 (m? 9Η) 3.69-3.83 (m, 2H) 6.96-7.17 (m, 1H) 7.28-7.41 (m 2H) 7·49-7·62 (m,2H) 9·53-9·74 (m,1H),順式/反式 85:15 中間物6 L·(經基曱盖)-3-苯基-1-氧雜-3-氮雜:癸烧_2_酮-56- 3- Φ-, 200838508 8-(Pylorylmethyl)-3-phenyl-1-oxa-3-azaspiro[4·5]nonane-2-one (Intermediate 6, 72.5 </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> </ br> The reaction was carried out for 2 hours, and the mixture was poured into a saturated solution of NaH.sub.3. Compound, used without re-refining. !H NMR (400 MHz5 CDC13): δ 1.33-2.34 (m? 9Η) 3.69-3.83 (m, 2H) 6.96-7.17 (m, 1H) 7.28-7.41 (m 2H) 7·49-7·62 (m,2H) 9·53-9·74 (m,1H), cis/trans 85:15 Intermediate 6 L·(via base cap)-3-phenyl- 1-oxa-3-aza: anthraquinone-2-ketone
15 將2-侧氧-3-苯基-1-氧雜-3-氮雜螺[4·5]癸烷_8_羧酸乙 酯(中間物1,110.0毫克,0·363毫莫耳),在氮氣層下,溶 解於热水的THF (2宅升)内,並冷卻至〇。〇,在此溫度下 20 滴入LiAlH4(lM,272微升,〇·272毫莫耳),再回溫至室 溫,加入乙醚及兩匙的NajO4乾燥劑;在室溫下將混合 -57· 200838508 物攪拌過夜,過濾,經乙醚洗滌,粗製品藉由快速矽膠層 析法純化,製得標題化合物(72.5毫克,76.5%); 咕 NMR (500 MHz,CDC13): δ 1.39 (3H,t),1·49-1·66 (5H,m),1·75-1·84 (2H,m),2·1〇-2·16 (2H,m)5 3·49-3·57 (21H,m),3·73 (2H,s),7·13 (1H,t)5 7·38 (2H,t),7·54 (2H, d); MS? m/z: 262 [M+H]+ 中間物7 (^_式)-2-侧_氧-3-苯基-1-氧雜_3-1雜螺「4.51癸烷-8-甲醛15 2-Ethyloxy-3-phenyl-1-oxa-3-azaspiro[4·5]decane-8-carboxylic acid ethyl ester (intermediate 1, 110.0 mg, 0·363 mmol) ), dissolved in hot water in THF (2 house liters) under a nitrogen blanket, and cooled to 〇. 〇, at this temperature 20 drops of LiAlH4 (lM, 272 μl, 〇 · 272 mmol), then warmed to room temperature, add diethyl ether and two spoons of NajO4 desiccant; mix at room temperature -57 · </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ),1·49-1·66 (5H,m),1·75-1·84 (2H,m),2·1〇-2·16 (2H,m)5 3·49-3·57 ( 21H,m),3·73 (2H,s),7·13 (1H,t)5 7·38 (2H,t),7·54 (2H, d); MS? m/z: 262 [M +H]+ Intermediate 7 (^_)-2- Side_Oxy-3-phenyl-1-oxa-3-1 Hetero” 4.51 decane-8-formaldehyde
在室溫下,將Dess-Martin過碘烷(15〇毫克,0.35毫莫 耳)加至攪拌中、溶解於二氣曱烷(3毫升)之(反式(羥基 甲基)-3-笨基-1-氧雜_3_氮雜螺[4·5]癸烧_2_酮(中間物8, 76 零克,0·29宅莫耳)之溶液内,所得混合物被攪拌1小時 後,加入飽和的亞硫酸鈉溶液(〇 5毫升)及碳酸氫鈉溶液(4 毫升)中止反應,攪拌5分鐘後,經由一種疏水性燒結物 (fliaseSep筒形物)過濾,有機層與更多的飽和之碳酸氫鈉 /谷液(4笔升)一起振搖後,經由一種疏水性燒結物 (PhaseSep筒形物)過濾,減壓下將有機層濃縮,殘留物於 -58· 200838508 二氧化矽上被層析,以30-50%的EtOAc/環己烷梯度溶 離’製得標題化合物,為一種白色固體(60毫克); H NMR (400 MHz,CDC13): δ 1·82 (4H,m),1·92 (2H, m),2.15 (2Η,m),2·52 (1Η,m),3·72 (2Η,s),7·15 (1Η,t), 7·39 (2Η,t),7·53 (2Η,d),9·74 (1Η,s)。Dess-Martin periodinane (15 mg, 0.35 mmol) was added to the mixture at room temperature and dissolved in dioxane (3 ml) (trans (hydroxymethyl)-3-phenyl) In the solution of ke-1-oxa-3_azaspiro[4·5]pyrroline-2-ketone (intermediate 8, 76 gram, 0·29 houser), the mixture was stirred for 1 hour. The reaction was quenched by the addition of saturated sodium sulfite solution (5 ml) and sodium bicarbonate solution (4 ml). After stirring for 5 minutes, it was filtered through a hydrophobic sinter (fliaseSep cartridge), and the organic layer was more saturated. Sodium bicarbonate/guar solution (4 liters) was shaken together, filtered through a hydrophobic sinter (PhaseSep tube), and the organic layer was concentrated under reduced pressure. The residue was taken on -58·200838508 cerium oxide. The title compound was obtained as a white solid (60 mg). 1·92 (2H, m), 2.15 (2Η, m), 2·52 (1Η, m), 3·72 (2Η, s), 7·15 (1Η, t), 7·39 (2Η, t ), 7·53 (2Η, d), 9·74 (1Η, s).
中間物SIntermediate S
酮ketone
ίο 1Η(/ 15 ^將氫化鋁鋰溶液(i.OM,溶在THF,0·39毫升,0.39毫 莫耳)’在-20C下,滴入至攪拌中、溶解在THF(1〇毫升) 内之(反式)-2-侧氧-3-苯基小氧雜冬氮雜螺[4·5]癸烧各缓 ^的U-二甲基乙基醋(中間物9,173毫克,〇·522毫莫 耳)’將所得混合物攪拌並回溫至1〇它,經1小時,加入 f外的氫化鋁鋰溶液G.0M,在THF内,〇·2〇毫升,〇·2〇毫 莫耳)並令反應混合物回溫至室溫,在室溫下攪拌3〇分鐘 後’加入乙醚(20晕升)並加入數滴水以中止反應,加入硫 ®夂鈉(1克)’激⑽拌3G分鐘’過濾,減壓下將濾液濃縮, 歹i召物於一氧化矽上被層析,以3〇_8〇%的Et〇Ac/環己烷 -59- 20 200838508 進行梯度溶離,製得標題化合物,為一穆白色固體(79毫 克); 4 NMR (400 MHz,CDC13): δ 1·17 (2H,m),I·42 (1H, brs)5 1·63 (1H,m),1·85 (2H,dt),1·99 (4H, m),3·56 (2H,d), 3·79 (2H,s),7·13 (1H,t),7·38 (2H,t),7·57 (2H,d)。 中間物9 Li-一甲基乙基(尽式則氣-3二笨基小 癸烷-8-羧酴醢Ίο 1Η(/ 15 ^ Lithium aluminum hydride solution (i.OM, dissolved in THF, 0. 39 ml, 0.39 mmol) - at -20 C, drip into stirring, dissolved in THF (1 mL) U-dimethylethyl vinegar (intermediate 9,173 mg, in the middle) (trans)-2-oxo-3-phenyloxyxanthroline[4·5] 522·522 mAh) 'The mixture was stirred and warmed to 1 Torr. After 1 hour, a solution of lithium aluminum hydride in G.0M was added, in THF, 〇·2 〇ml, 〇·2〇 Millenol) and let the reaction mixture warm to room temperature, stir at room temperature for 3 minutes, then add diethyl ether (20 halo) and add a few drops of water to stop the reaction, add sulfur® sodium citrate (1 g) (10) After mixing for 3 G minutes, the filtrate was concentrated, and the filtrate was concentrated under reduced pressure. The title compound was chromatographed on ruthenium pentoxide and subjected to gradient elution with 3 〇 -8 % of Et 〇 Ac / cyclohexane - 59 - 20 200838508. The title compound was obtained as a white solid (79 mg); 4 NMR (400 MHz, CDC13): δ 1·17 (2H, m), I·42 (1H, brs)5 1·63 (1H, m),1·85 (2H,dt),1·99 (4H, m),3·56 (2H,d), 3·79 (2H,s),7·13 (1H t), 7 · 38 (2H, t), 7 · 57 (2H, d). Intermediate 9 Li-monomethylethyl (except gas-3 diphenyl decane-8-carboxyindole)
1010
15 對置於圓底燒瓶中之(順式)_2_侧氧苯基-1-氧雜-3· 氮雜螺[4.5]癸烧各竣暖(中間物1〇, Ο,%克,M毫莫耳)、 二I基甲醯胺(0.1毫升)及四氫呋喃(8毫升)之混合物,滴 =氧氯化磷(0.15毫升,^毫莫耳),混合物被加熱至40°C ^予以跡2小時,在此期間,在另—小玻璃瓶授拌四甲 乙二胺(〇.73宅升,4 8亳莫耳)、第三丁醇毫升,21 升),將摔轴、入为見,零莫耳)及四氫呋喃(2毫 n)將燒升瓦冷郃至室溫,被撸挑τ ^ 容物至瓶中之中間物酸氣:C ’滴入小玻璃中之内 乳化物喊内,齡物被加熱至 20 200838508 35°C,攪拌18小時,加水稀釋,以乙酸乙酯萃取兩遍, 合併有機層,洗蘇(水、稀鹽酸、水)、經一種疏水的膜過 濾,減壓下濃縮,製得粗製產品(0·47克),粗製品藉由快 速管柱層析法純化(矽膠;環己烷-乙酸乙酯,10:1);合併 5 僅含較流動較快的異構物之劃分,於真空下濃縮,製得呈 粘稠油質狀之標題化合物,靜置後析出結晶(0.185克, 40%); lR NMR (400 MHz, CDC13): δ 7.53 (2Η, d)? 7.34 (2Η5 t),7·09 (1Η,t),3·73 (2Η,s)5 2·37 (1Η,m),2·08-1·99 (2Η, • m),1.96-1.88 (2H,m),1·87-1·78 (2H,m),1·72-1·61 (2H,m) 4〇 及 1.44(9H,s); UPLC-MS: 0.85 分鐘,m/z 331 [M+H]+ 中間物10 (順式)-2-侧氣-3-茉基-1-氣雜-3-氮雜螺『4.51癸烷-8-羧酸15 pairs of (cis)_2_ side oxyphenyl-1-oxa-3·azaspiro[4.5] simmered in a round bottom flask (intermediate 1 〇, Ο, % gram, M Mixture of mM mesylamine (0.1 ml) and tetrahydrofuran (8 ml), drop = phosphorus oxychloride (0.15 ml, ^ mmol), the mixture was heated to 40 ° C. 2 hours, during which time, in another small glass bottle, tetramethylethylenediamine (〇.73 house liter, 4 8 亳mol), third butanol ML, 21 liters, will be broken. , zero molars and tetrahydrofuran (2 millin) will be cooled to room temperature, picked up τ ^ contents to the middle of the bottle of acid gas: C 'drip into the small glass within the emulsion shout The aged material was heated to 20 200838508 35 ° C, stirred for 18 hours, diluted with water, extracted twice with ethyl acetate, combined with organic layer, washed with water (diluted hydrochloric acid, water), filtered through a hydrophobic membrane. Concentrated under reduced pressure to give a crude product (0·47 g). The crude product was purified by flash column chromatography (purified: hexane-ethyl acetate, 10:1); Fast isomerization The title compound was obtained as a viscous oily substance, which crystallised (0.185 g, 40%) after standing; lR NMR (400 MHz, CDC13): δ 7.53 (2Η, d)? 7.34 (2Η5 t ),7·09 (1Η,t),3·73 (2Η,s)5 2·37 (1Η,m),2·08-1·99 (2Η, • m),1.96-1.88 (2H,m ),1·87-1·78 (2H,m),1·72-1·61 (2H,m) 4〇 and 1.44(9H,s); UPLC-MS: 0.85 minutes, m/z 331 [M +H]+ Intermediate 10 (cis)-2-Side-3-Methyl-1-oxa-3-azaspiro"4.51 decane-8-carboxylic acid
15 對溶解於曱醇(10毫升)之(順式)-2-側氧-3-苯基-1-氧 雜-3-氮雜螺[4.5]癸烷-8-羧酸乙酯(中間物11,0.45克,1.5 毫莫耳)溶液,攪拌中,滴入溶解於水(2毫升)中之氫氧化 2〇 鋰(0.18克)溶液,攪拌1小時,再靜置18小時,加入稀鹽 -61 - 200838508 酸(1M)酸化,以乙酸乙酯萃取兩遍,合併有機層,經水洗 滌,經由一種疏水的膜過濾並在真空下濃縮,製得標題化 合物(0.393克,96%),為一種白色固體。 NMR (400 MHz? CDC13): δ 7.54 (2Η, d), 7.38 (2Η? 5 t),7·14 (1Η,t),3·75 (2Η,s),2·43 (1Η,m),2·19 (1Η,m), 2·16 (1H,m),2·08 (1H,m),2·06·1·98 (3H,m)及 1·65 (2H, m);15 pairs of (cis)-2-oxo-3-phenyl-1-oxa-3-azaspiro[4.5]decane-8-carboxylic acid ethyl ester dissolved in decyl alcohol (10 ml) a solution of 11, 0.45 g, 1.5 mmol, while stirring, a solution of lithium ruthenium hydroxide (0.18 g) dissolved in water (2 ml) was added dropwise, stirred for 1 hour, and allowed to stand for another 18 hours. Salt-61 - 200838508 Acidic acid (1M), EtOAc (EtOAc) , a white solid. NMR (400 MHz? CDC13): δ 7.54 (2Η, d), 7.38 (2Η? 5 t), 7·14 (1Η, t), 3·75 (2Η, s), 2·43 (1Η, m) , 2·19 (1Η, m), 2·16 (1H, m), 2·08 (1H, m), 2·06·1·98 (3H, m) and 1.65 (2H, m);
10 UPLC-MS: 0.62 分鐘,m/z 274 [M-H]。 中間物11及12 爐式)-2-側氧-3-笨基小氣雜-3·氮雜螺「4.51癸烷-8-羧酸乙 Ιϋ中間物11)以及(反式V2-侧氣-3-茉某小氳雜-3-氮雜螺 「4.51癸烷-8-羧酸乙酯(中間物12)10 UPLC-MS: 0.62 min, m/z 274 [M-H]. Intermediates 11 and 12 furnace type)-2- side oxygen-3-stupyl small gas hetero-3·azaspiro"4.51 decane-8-carboxylic acid acetamidine intermediate 11) and (trans V2-side gas - 3-Methyl chlorpyrifos-3-azaspane "4.51 decane-8-carboxylic acid ethyl ester (intermediate 12)
15 方法11a 將4-羥基-4-[(苯基胺基)曱基]環己烷羧酸乙酯(以類 似於中間物3的製法製備,190·5毫克,〇·68毫莫耳)溶解於 热水的DCM(10毫升)’在氛氣層下,冷卻,在此 溫度下,加入ΤΕΑ(189·38微升,1·36毫莫耳)及三光氣 •62- 20 200838508 (100.691毫克,0·34毫莫耳),在-78°C下攪拌2·5小時,力σ 入更多的三光氣(100.0毫克,0.337毫莫耳),再將混合物 攪拌2小時(直到反應完全),對反應加入飽和的NIl4C1溶 液,以DCM萃取;有機層在Na2S04上乾燥,過濾及在真 5 空下被濃縮,製得殘留物(175毫克),其藉由快速石夕膠層 析法被純化(化合物Rf=0.27,環己烷:Et〇Ac :3),純化 後,取得兩種分開的異構物:異構物1(中間物I2,32·9毫 克)及異構物2 (中間物11,113·2毫克),第/個化合物相 當於反式異構物,第二個化合物相當於順式異構物; 40 異構物1 (反式),中間物12: 4 NMR (500 MHz,CDC13): δ7·55 (2Η,d),7·38 (2Η,0, 7·14 (1Η,t),4·16 (2Η,q)5 3·78 (2Η,s),2·46-2·57 (1Η,m), 2·04-2·17 (2H,m),1·84-2·02 (4H,m),ΐ·70-1·81 (2H,m), 15 1.28 (3H5 t); MS: m/z 304 [M+H]+。 異構物2 (順式),中間物11: 4 NMR (500 MHz,CDC13): δ 7·54 (2H,d),7.38 (2H, 2〇 t),7·14 (1H,t),4·15 (2H,q),3.74 (2H,s),2.30-2.42 (1H,m)5 2·15 (2H,d),1·91-2·09 (4H,m),1.58+69 (2H,td),1·28 (3H,t); MS: m/z 304 [M+H]+。 方法11 b -63- 200838508 在一個圓底燒瓶中,將(反式)-2-侧氧-1-氧雜_3_氮雜螺 [4·5]癸烷-8-羧酸乙酯(以製備中間物15之類似方法製備, 〇·21克,0.924亳莫耳)溶解於甲苯(2」亳升)後,加入碘苯 (〇·207毫升,i848毫莫耳)、碳酸铯(〇·753克,2·3ι〇毫莫 5 耳)、碘化亞銅m(8.8〇毫克,〇·〇46毫莫耳)及反式q 2—二胺 基環己烷(0.0H毫升,0.092亳莫耳),在8〇。〇下將混Z物 攪拌過夜(共經24小時),混合物冷卻至室溫後,置於水(2〇 鲁毫升)及乙酸乙酯(2x20毫升)中分配,合併的有機層經水 1 洗滌後,經一種相分離過濾器過濾,減壓下濃縮,粗製品 J〇 藉由管柱層析法純化(矽膠;環己烷/乙酸乙酯,1:〇至^〇·1 至6:1,階段式梯度),製得中間物13(0165克,59%)及中 間物 12 (0.017 克,7%)。 中間物13: 15 'Η NMR (400 MHz5 CDC13): δ 7.56 (2Η5 d)5 7.39 (2Η 鲁 t)? 7.15 (1H? t)5 4.17 (2H? q)? 3.78 (2H5 s)? 2.48^2.57 (1Η? m) 2·〇7-2·18 (2H,m),1·85-2·03 (4H,m),1·7(Μ·83 (2H,m) (3H5 t); ’ ’ UPLC-MS: 0.75 分鐘,m/z 304 [M+H]' 20 .中間物12:15 Method 11a Ethyl 4-hydroxy-4-[(phenylamino)indenyl]cyclohexanecarboxylate (prepared as a procedure analogous to Intermediate 3, 190·5 mg, 〇·68 mmol) DCM (10 ml) dissolved in hot water was cooled under the atmosphere, and at this temperature, yttrium (189.38 μl, 1.36 mmol) and triphosphorus were added. 62- 20 200838508 (100.691 Mg, 0·34 mmol; stir at -78 °C for 2.5 hours, force σ into more triphosgene (100.0 mg, 0.337 mmol), and stir the mixture for 2 hours (until the reaction is complete) To the reaction, a saturated solution of NIl4C1 was added, and the mixture was extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give residue (175 mg) Purified (compound Rf=0.27, cyclohexane: Et 〇Ac: 3), after purification, two separate isomers were obtained: isomer 1 (intermediate I2, 32·9 mg) and isomer 2 (intermediate 11,113·2 mg), the first compound corresponds to the trans isomer, the second compound corresponds to the cis isomer; 40 isomer 1 (trans), intermediate 12 : 4 NMR (500 MHz, CDC13): δ7·55 (2Η,d),7·38 (2Η,0, 7·14 (1Η,t),4·16 (2Η,q)5 3·78 (2Η ,s),2·46-2·57 (1Η,m), 2·04-2·17 (2H,m),1·84-2·02 (4H,m),ΐ·70-1·81 (2H,m), 15 1.28 (3H5 t); MS: m/z 304 [M+H]+. Isomer 2 (cis), Intermediate 11: 4 NMR (500 MHz, CDC13): δ 7 · 54 (2H, d), 7.38 (2H, 2〇t), 7·14 (1H, t), 4·15 (2H, q), 3.74 (2H, s), 2.30-2.42 (1H, m) 5 2·15 (2H,d),1·91-2·09 (4H,m), 1.58+69 (2H,td),1·28 (3H,t); MS: m/z 304 [M+ H]+. Method 11 b -63- 200838508 In a round bottom flask, (trans)-2-oxo-1-oxa-3-azaspiro[4·5]nonane-8-carboxylate Ethyl acetate (prepared in a similar manner to the preparation of intermediate 15, 〇 21 g, 0.924 Torr) dissolved in toluene (2 liters), then added with iodobenzene (〇·207 ml, i848 mmol), Barium carbonate (〇·753 g, 2·3ι〇5 ears), cuprous iodide m (8.8〇 mg, 〇·〇46 mmol) and trans q 2-diaminocyclohexane (0.0) H ml, 0.092 亳 Mo ear), at 8 〇. The mixture was stirred overnight (for a total of 24 hours), and the mixture was cooled to room temperature, then partitioned between water (2 mL) and ethyl acetate (2×20 mL). After that, it was filtered through a phase separation filter, concentrated under reduced pressure, and the crude product was purified by column chromatography (yield: cyclohexane/ethyl acetate, 1: 〇 to 〇·1 to 6:1) Intermediate gradient 13 (0165 g, 59%) and intermediate 12 (0.017 g, 7%). Intermediate 13: 15 'Η NMR (400 MHz5 CDC13): δ 7.56 (2Η5 d)5 7.39 (2Η 鲁 t)? 7.15 (1H? t)5 4.17 (2H? q)? 3.78 (2H5 s)? 2.48^ 2.57 (1Η? m) 2·〇7-2·18 (2H,m),1·85-2·03 (4H,m),1·7(Μ·83 (2H,m) (3H5 t); ' ' UPLC-MS: 0.75 minutes, m/z 304 [M+H]' 20 . Intermediate 12:
4 NMR (400 MHz,CDC13): δ 7.55 (2H,d),7·39 (2H t),7.15 (1H,t),4.17 (2H,q),3·75 (2H,s),2.32-2,43 (1H,_ 2.12-2-22 (2H,m),1.90-2·10 (4H,m),1·58-1·7〇 (2H,m),’ -64- 200838508 1.29 (3H,t); UPLC-MS: 0·74 分鐘,m/z 304 [M+H]、 中間物13 5 4-Π-甲基-2-吡啶基)-1,3-噻唑-2-胺4 NMR (400 MHz, CDC13): δ 7.55 (2H, d), 7·39 (2H t), 7.15 (1H, t), 4.17 (2H, q), 3·75 (2H, s), 2. 2,43 (1H, _ 2.12-2-22 (2H,m), 1.90-2·10 (4H,m),1·58-1·7〇(2H,m),' -64- 200838508 1.29 ( 3H, t); UPLC-MS: 0·74 min, m/z 304 [M+H], intermediate 13 5 4-indole-methyl-2-pyridyl)-1,3-thiazol-2-amine
將1-(3-曱基-2-吼啶基)乙酮(0.343克,2.54毫莫耳,為 可購得之化合物)、硫脲(0.042克,0.55毫莫耳)及碘(0.103 克,0.40毫莫耳),溶解於1,4-二畤烷(6毫升)後,混合物於 ίο l〇〇°C下攪拌3小時,再加入一些硫脲(0.021克,0.275毫 莫耳)及碘(0.05克,0.20毫莫耳),在100°C下再攪拌4小 時,加入飽和的NaHC03水溶液,混合物以DCM萃取, 有機層以硫代硫酸鈉水溶液及水洗滌,有機萃取層在真空 φ 下濃縮,製得殘留物,殘留物藉由石夕膠層析法純化,以環 15 己烷:EtOAc 100:0至60:40溶離,製得標題化合物,為一 種棕色固體(198毫克,40%); NMR (400 MHz, CDC13): δ 2.54 (s5 3 Η) 4.92-5.12 (br. s5 2H) 6.92-6.94 (br. s, 1Π) 7.11-7.18 (m? 1H) 7.51-7.59 (m,1H) 8·47-8·55 (m,1H)。 中間物14 -65- 20 200838508 3-溴-2-氟吡啶1-(3-Mercapto-2-acridinyl)ethanone (0.343 g, 2.54 mmol, a commercially available compound), thiourea (0.042 g, 0.55 mmol) and iodine (0.103 g) , 0.40 mmol, dissolved in 1,4-dioxane (6 ml), the mixture was stirred at ίο 1 ° C for 3 hours, then some thiourea (0.021 g, 0.275 mmol) and Iodine (0.05 g, 0.20 mmol), stirred at 100 ° C for further 4 hours, a saturated aqueous solution of NaHCO3 was added, the mixture was extracted with DCM, and the organic layer was washed with aqueous sodium thiosulfate and water. Concentration, the residue was purified by EtOAc EtOAc (EtOAc) NMR (400 MHz, CDC13): δ 2.54 (s5 3 Η) 4.92-5.12 (br. s5 2H) 6.92-6.94 (br. s, 1Π) 7.11-7.18 (m? 1H) 7.51-7.59 (m , 1H) 8·47-8·55 (m, 1H). Intermediate 14 -65- 20 200838508 3-Bromo-2-fluoropyridine
將3-溴-2-硝基吡啶(1克,4.93毫莫耳)溶解於N,N—二 曱基曱醯胺(ίο毫升)後,加入四丁基銨氟化物(8 96毫升, 5 9·85毫莫耳),在室溫了將此溶液攪拌5小時,將此暗紅- 方示色反應/心合物倒入至50宅升的1:1之水盘EtOAc之混 鲁合液内’有機層以水及鹽水洗務兩遍,萃取物經Na2s〇4 乾燥,過濾,濃縮,殘留物藉由矽膠管桎2514則〇姐弘純 化’以壞己烧/EtOAc的混合物溶離,所要產品在25% ίο EtOAc下被流洗出來,製得313毫克的3_溴_2_氟吡啶。 ^-NMR (400 MHz? DMSO-t/6): δ 8 16 (1Η,句, 7.95-8.04 (1Η,m),7·08-7·14 (1Η,m)。 中間物16 • (及式上·2ϋ羞小氧雜-3-氮雜螺「4·51癸羧酸乙酯(中間 跑~四互1^^)-2-侧氧-1-氣雜-3-氮雖屢「451癸炫-8-鍵酸 乙酯1中1❸After dissolving 3-bromo-2-nitropyridine (1 g, 4.93 mmol) in N,N-didecylguanamine (ίο ml), tetrabutylammonium fluoride (8 96 ml, 5 was added) 9.85 millimolar), the solution was stirred for 5 hours at room temperature, and the dark red-square color reaction/heart complex was poured into a 50 liter 1:1 water tray of EtOAc. The inner layer of the organic layer was washed twice with water and brine. The extract was dried over Na2s 〇4, filtered and concentrated, and the residue was purified by the mixture of 矽 弘 桎 14 14 14 14 以 以 以 以 以 以 以 , , The product was flushed under 25% EtOAc to yield 313 mg of 3-bromo-2-fluoropyridine. ^-NMR (400 MHz? DMSO-t/6): δ 8 16 (1Η, sentence, 7.95-8.04 (1Η, m), 7·08-7·14 (1Η, m). Intermediate 16 • (and On the formula, 2 ϋ 小 small oxa-3-azane snail "4·51 癸 carboxylic acid ethyl ester (middle run ~ four mutual 1 ^ ^) -2- side oxygen-1-gas -3- nitrogen 451癸Hyun-8-bonded acid ethyl ester 1 in 1❸
200838508 在室溫下,將第三-丁氧化鉀(23.14克,206毫莫耳)分 批加入至攪拌中、溶解在DMF(200毫升)之胺基曱酸乙酯 (27·6克,309毫莫耳)溶液,所得之霧狀的混合物被攪拌1 小時’再加入溶解於DMF(50毫升)内之1-氧雜螺[2.5]辛 5 烷-6-羧酸乙酯(依類似於中間物4方法4b之方式製備,19 克,103毫莫耳)溶液,反應混合物被加熱至130°C,過夜 (〜18小時),冷卻後,加入飽和的NaCl溶液(20毫升),以 AcOEt萃取(4 X 1〇〇毫升),合併有機層,乾燥(Na2S04), I 過濾,濃縮,製得一種淡黃色油質物,殘留物經由Biotage -ίο 純化(環己烧:AcOEt,開始於1:1至純的AcOEt; 65M管 柱),製得中間物15(8.24克)及中間物16(4·36克); 中間物15 lR NMR (400 MHz, CDC13): δ 5.39 (1Η5 brs)? 4.15 (2Η? 15 q),3·37 (2Η,s),2·47 (1Η,sept),2·01-2·11 (2Η,m), 1·80-1·95 (4Η,m)5 1·62-1·74 (2Η,m),1·27 (3Η,t)。 中間物16 lR NMR (400 MHz, CDC13): δ 5.27 (1H, brs)? 4.15 (2H? 20 q),3·32 (2H,s),2.28-2.37 (1H,m),2.13 (2H,brd), 1·85-2·05 (4H,m),1·53 (2H,td),1.27 (3H,t)。 中間物17 (反式V8-(羥某甲基)-1-氣雜-3-氮雜壤『4.51癸烷-2-酮 -67- 200838508200838508 Addition of potassium tert-butoxide (23.14 g, 206 mmol) to a stirred solution of ethyl amide in DMF (200 ml) at room temperature (27·6 g, 309) Milligram) solution, the resulting misty mixture was stirred for 1 hour' and then added to 1-oxaspiro[2.5]octane-5-carboxylic acid ethyl ester dissolved in DMF (50 mL) (similar to Intermediate 4 was prepared in the manner of Method 4b, 19 g, 103 mmoles. The reaction mixture was heated to 130 ° C overnight (~18 hours). After cooling, a saturated NaCl solution (20 mL) was added to AcOEt. Extraction (4 X 1 mL), the combined organic layers, dried (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1 to pure AcOEt; 65M column), intermediate 15 (8.24 g) and intermediate 16 (4·36 g) were obtained; Intermediate 15 lR NMR (400 MHz, CDC13): δ 5.39 (1Η5 brs)? 4.15 (2Η? 15 q),3·37 (2Η,s),2·47 (1Η,sept),2·01-2·11 (2Η,m), 1·80-1·95 (4Η,m) 5 1·62-1·74 (2Η, m), 1·27 (3Η, t). Intermediate 16 lR NMR (400 MHz, CDC13): δ 5.27 (1H, brs)? 4.15 (2H? 20 q), 3·32 (2H, s), 2.28-2.37 (1H, m), 2.13 (2H, Brd), 1·85-2·05 (4H, m), 1.53 (2H, td), 1.27 (3H, t). Intermediate 17 (trans V8-(hydroxymethyl)-1-gas-3-nitrogen "4.51 decane-2-one -67- 200838508
在〇°C下,將氳化鋁鋰(1·0Μ,在11^内,22.00毫升, 22.00毫莫耳)加至溶解於四氫呋喃(THF)(50毫升)之(反 式)-2-側氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-羧酸乙酯(中間物 _ 15, 2500毫克,11.00毫莫耳)溶液内,在加入第1當量的 時,可見到產生氣體,所得混合物被回溫至室溫,在-20°C 下加入Na2S〇4 X 10 (20克),靜置1小時,回溫至室溫, 過濾所得之混合物,以二氯曱烷(500毫升)及二氯曱烷 /MeOH 90/10 (150毫升)洗滌,除去溶劑後,製得標題之 1〇 產物,為一種無色固體(2.4克)。 iH-NMR (400 MHz,DMSO,: δ 4.60 (1H,brs), 3.11-3.27 (4H,m),1·65-1·80 (4H,m),1.51 (2H,td), 1·29-1·41 (1H,m),0·9(Μ·04 (2H,m); UPLC-MS: 0.35 分鐘, _ 186 [M+H]+。 中間物18 (反式)-2-侧氣-1-氣雜-3-氮雜螺「4.51癸烷-8-甲醛Lithium aluminum telluride (1·0Μ, within 11^, 22.00 ml, 22.00 mmol) was added to the (trans)-2- side dissolved in tetrahydrofuran (THF) (50 ml) at 〇 °C In the solution of ethyl oxy-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (intermediate -15, 2500 mg, 11.00 mmol), visible when the first equivalent is added To produce a gas, the resulting mixture was warmed to room temperature, and Na2S〇4 X 10 (20 g) was added at -20 ° C, allowed to stand for 1 hour, warmed to room temperature, and the resulting mixture was filtered to dichloropurine. The title compound was obtained as a colorless solid (yield: 2.4 g). iH-NMR (400 MHz, DMSO, δ 4.60 (1H, brs), 3.11-3.27 (4H, m), 1.65-1·80 (4H, m), 1.51 (2H, td), 1·29 -1·41 (1H,m),0·9(Μ·04 (2H,m); UPLC-MS: 0.35 min, _ 186 [M+H]+. Intermediate 18 (trans)-2- side Gas-1-gas hetero-3-azaspiro"4.51 decane-8-formaldehyde
-68- 200838508 將(反式)-8-(羥基曱基)-1-氧雜-3-氮雜螺[4.5]癸烷-2_ 酮(中間物17,1.2克,5.51毫莫耳)與卩8-«8又醯胺(11.〇1克, U·01毫莫耳)一起在二氯曱烷(100毫升)内、室溫下搖動, 經24小時,再加入另1〇當量之pS-IBx醯胺,進行再24 5 小時之反應,過濾,以大量二氯曱烷(500毫升)洗滌,有 機層被濃縮’製得約1·3克之粗製油質物,經Biotage SP1 純化,於預以100% EtOAc調理過之一種25M矽膠筒内, 以EtOAc (100%)溶離,回收得的標題化合物(240毫克)為 一種無色固體。 10 咕 NMR (400 MHz,CDC13): δ 9·73 (1H,s),5·34 (1H, brs),3·32 (2Η,s),2·48 (1Η,五重峰),2·06-2·15 (2Η,m), 1·88-1·96 (2Η,m),1·71-1·82 (4Η, m) 〇 或者,中間物18可以類似於製備中間物7之方式製 備,替代(反式)-8-(羥基甲基)-3-苯基-1-氧雜-3-氮雜螺[4.5] 15 癸烧-2-酮成(反式)_8-(經基曱基)_1_氧雜-3 -氮雜螺[4.5]癸 烷-2-酮(中間物17)而製之。 _ lR NMR (400 MHz, DMSO-i/6): δ 1.44-1.57 (m? 2Η) 1·61·1·77 (m,4Η) 1·84-1·94 (m,2Η) 2.34_2·42 (m,1Η) 2.49-2.52 (m,1H) 3·20 (d,2H) 9.60 (d,1H); UPLC-MS: 2〇 0.38 分鐘,184 [M+H]+ 中間物19 式V8-q『l_(2·氟苯基)-1Η-吡唑-3-某1胺某}甲基VI-氳 雜-3-氤雜嫘「4.5Ί癸烷-2-酮 -69- 200838508-68- 200838508 (trans)-8-(hydroxyindenyl)-1-oxa-3-azaspiro[4.5]decane-2-one (intermediate 17, 1.2 g, 5.51 mmol)卩8-«8 decylamine (11. 〇1 g, U·01 mmol) was shaken in dichlorodecane (100 ml) at room temperature for another 24 hrs. pS-IBx decylamine was reacted for a further 24 hours, filtered, washed with a large amount of dichloromethane (500 mL), and the organic layer was concentrated to give a crude oil of about 1.3 g, purified by Biotage SP1 The title compound (240 mg) was obtained as a colorless solid. 10 咕 NMR (400 MHz, CDC13): δ 9·73 (1H, s), 5·34 (1H, brs), 3·32 (2Η, s), 2·48 (1Η, quintuple), 2 ·06-2·15 (2Η,m), 1·88-1·96 (2Η,m),1·71-1·82 (4Η, m) 〇 or, the intermediate 18 can be similar to the preparation of the intermediate 7 Prepared by substituting (trans)-8-(hydroxymethyl)-3-phenyl-1-oxa-3-azaspiro[4.5] 15 oxime-2-one to (trans)_8- (based on fluorenyl)_1_oxa-3-azaspiro[4.5]nonan-2-one (intermediate 17). _ lR NMR (400 MHz, DMSO-i/6): δ 1.44-1.57 (m? 2Η) 1·61·1·77 (m, 4Η) 1·84-1·94 (m, 2Η) 2.34_2· 42 (m,1Η) 2.49-2.52 (m,1H) 3·20 (d,2H) 9.60 (d,1H); UPLC-MS: 2〇0.38 min,184 [M+H]+ Intermediate 19 V8 -q『l_(2·fluorophenyl)-1Η-pyrazole-3-one 1 amine}methyl VI-oxa-3-oxanthene "4.5 oxane-2-one-69- 200838508
1010
15 2015 20
在室溫下,將(反式)-2-侧氧氧雜_3_氮雜螺 -8-曱醛(中間物18, 240毫克,iwo毫莫耳)、j二 基)-1Η-吼嗤-3-胺(232毫克,以❻毫莫耳)(H J.Org.Cliem. 2005, 70, 922中揭露之方法製備)及昱丙 鈦(IV)(〇.768毫升,2.62毫莫耳)攪拌於二氯甲烷&毫升卜 過夜,然後加入氫硼化鈉(149毫克,3.93毫莫耳)及乙醇(2 毫升)(小心,H2),所得混合物再被攪拌5小時後,加入二 氯曱烧(150毫升)並以飽和的NajjC〇3(3毫升)中止反應, 再經一種過濾管過濾,除去溶劑後,殘留物(45〇毫克)以 Biotage SP1純化,經過一種25MKP-NH筒形物,以1〇〇〇/。(trans)-2-oxooxa-3-azaspiro-8-furfural (intermediate 18, 240 mg, iwo millimol), j diyl)-1Η-吼 at room temperature Indole-3-amine (232 mg, ❻ millimolar) (prepared by the method disclosed in H J. Org. Cliem. 2005, 70, 922) and bismuth titanium (IV) (〇.768 ml, 2.62 mmol) The ear was stirred in dichloromethane & ml b overnight, then sodium borohydride (149 mg, 3.93 mmol) and ethanol (2 ml) (caution, H2) were added and the mixture was stirred for 5 hours and then added. Dichlorohydrazine (150 ml) and quenched with saturated NajjC 3 (3 mL), then filtered through a filter to remove the solvent and the residue (45 mg) was purified on Biotage SP1, passed a 25MKP-NH Tubular, to 1 〇〇〇 /.
EtOAc溶離,製得標題化合物,為無色固體(350毫2克)。 lR NMR (400 MHz5 CDC13): δ 7.82-7.87 (2Η, m)9 7·11-7·24 (3Η,m),5·95 (1Η,brs),5·82 (1Η,d),3·98 (1Η, brs),3·39 (2H,s),3·15 (2H,d),1.94-2.03 (4H,m),1·65-1·85 (3H,m),1.03-1.18 (2H,m); UPLC-MS: 0·67 分鐘,345 [M+H]+ 〇 中間物20 200838508 么式)-3-(U基nn基^激氧小氲雜义氣 [4·51癸烧-8-#酸乙酉旨 ‘ ρ vp V· ^0¾ 將(反式>2-侧氧-1·氧雜-3-氮雜螺[4·5]癸烷羧酸乙 酯(中間物15, 200毫克,〇·88Ό毫莫耳卜^碘小甲基·g 吡唑(0.177晕升,1.760亳莫耳)、Ν,Ν,_二曱基],2_乙二胺 (0.028笔升,0.264宅莫耳)、碘化亞銅⑴(5〇3毫克,〇·264 =莫耳)及碳酸鉀(438毫克,3·17毫莫耳)懸浮於•二噚 、元(毛升)後,以被波知射,在13〇 ◦下加熱兩次分鐘, 再於150 C下加熱兩次30分鐘,反應混合物以乙酸乙酯 (2〇〇耄升)稀釋,經水(2〇毫升)、〇·25Μ氯化氫水溶液(25 耄升)、飽和的碳酸氫鈉水溶液(25毫升)及鹽水(25毫升) 洗滌,有機層以硫酸鈉乾燥,過濾,濃縮,殘留物在矽膠 上進行層析,以環己烷/乙酸乙酿9/1至3/7溶離,所要產 物於1/1之環己炫/乙酸乙酯溶離,收集得180毫克的標題 化合物。 4 NMR (400 MHz,CDC13): δ 7·29 (1Η,d),6·64 (1Η, d),4.16 (2H,qua),3·86 (2H,s),3·83 (3H,s),2·47 (1H,sept), 2·〇4_2·15 (2H,m),1.92-2.01 (2H,m),1·87 (2H,td), -71- 200838508 1·68_1·81 (2H,m),1·28 (3H5 t); UPLC-MS: 0·63 分鐘,308 [M+H]+ 〇 中間物21 5 (反式基―1廷二吼JO-2-侧氣-1-氳雜-3-i.雜虫累 [4.51癸烷士農酸乙皇The title compound was obtained as a colorless solid (350 m). lR NMR (400 MHz5 CDC13): δ 7.82-7.87 (2Η, m)9 7·11-7·24 (3Η,m),5·95 (1Η,brs),5·82 (1Η,d),3 ·98 (1Η, brs), 3·39 (2H, s), 3·15 (2H, d), 1.94-2.03 (4H, m), 1.65-1·85 (3H, m), 1.03- 1.18 (2H,m); UPLC-MS: 0·67 minutes, 345 [M+H]+ 〇Intermediate 20 200838508 式式)-3-(U-based nn-based 激 激 氲 [ [ [ [ 51癸烧-8-#酸乙酉的' ρ vp V· ^03⁄4 (trans > 2- side oxy-1·oxa-3-azaspiro[4·5]decanecarboxylic acid ethyl ester ( Intermediate 15, 200 mg, 〇·88 Ό 莫 ^ ^ iodine small methyl · g pyrazole (0.177 halo, 1.760 亳 Mo), Ν, Ν, _ dimethyl hydrazine, 2 ethanediamine ( 0.028 pens, 0.264 house moles), cuprous iodide (1) (5〇3 mg, 〇·264 = moule) and potassium carbonate (438 mg, 3.17 mmol) suspended in • 噚, yuan ( After the wool is lifted, it is heated by the wave, heated at 13 Torr for two minutes, and then heated at 150 C for 30 minutes. The reaction mixture is diluted with ethyl acetate (2 liters) and passed through water ( 2 〇 ml), 〇·25Μ aqueous hydrogen chloride solution (25 liters), saturated sodium bicarbonate The organic layer (25 ml) and brine (25 ml) were washed, the organic layer was dried over sodium sulfate, filtered, and concentrated, and the residue was chromatographed on a silica gel, hexanes/acetic acid, 9/1 to 3/7, The desired product was dissolved in 1/1 of hexane/ethyl acetate to afford 180 mg of the title compound. 4 NMR (400 MHz, CDC13): δ 7·29 (1 Η, d), 6·64 (1 Η, d ), 4.16 (2H, qua), 3·86 (2H, s), 3·83 (3H, s), 2·47 (1H, sept), 2·〇4_2·15 (2H, m), 1.92 2.01 (2H,m),1·87 (2H,td), -71- 200838508 1·68_1·81 (2H,m),1·28 (3H5 t); UPLC-MS: 0·63 minutes,308 [ M+H]+ 〇Intermediate 21 5 (trans-based -1 廷二吼JO-2-lateral gas-1-noise-3-i. Insects tired [4.51 decane sinensis
將(反式)_2-侧氧+氧雜I氮雜螺[4.5]癸烷-8-羧酸乙 1〇 酯(中間物I5,100毫克,0.440毫莫耳)、3-碘_1_曱基-1H- 吡唑(0.088毫升,0·880毫莫耳)、N,NT-二曱基-1,2-乙二胺 # (0.014毫升,0·132毫莫耳)、碘化亞銅(1)(25.1毫克,0.132 毫莫耳)及碳酸鉀(219毫克,1.584毫莫耳)懸浮於1,4-二啐 烷(4毫升)後,混合物以微波照射,在130°C下加熱兩次 15 30分鐘,再於15〇°C下加熱兩次30分鐘,在最後的循環 中,已可見到一些差向立體異構化(根據UPLC-MS分析, 約有2-3%),反應混合物以乙酸乙酯(70毫升)稀釋,經水 (20亳升)、0.25M氯化氫水溶液(20毫升)、飽和的碳酸氫 鈉水溶液(20毫升)及鹽水(20毫升)洗滌,有機層以硫酸鈉 -72- 200838508 乾燥,過濾,濃縮,殘留物在矽膠上進行層析,以環己烷 /乙S文乙S曰9/1至3/7浴離,所要產物於環己烧/乙酸乙酯 為1/1下被溶離’收集得108毫克的標題化合物。 H NMR (400 MHz,CDC13): δ 7.29 (1H,d),6.64 (1H, 5 d)? 4.16 (2H? qua)5 3.86 (2H9 s)5 3.83 (3H5 s)? 2.47 (1H, sept), 2·04-2·15 (2H,m),1.92-2.01 (2H,m),1.87 (2H,td), 1·68-1·81 (2H,m),1·28 (3H,t); UPLC_MS: 0.63 分鐘,308 [M+H]+ 〇 JO 中間物22 L反Α·)-8_(經基甲基)_3·(1_甲某-iH-p比峻某)小氣雜 氮雜螺[4.51癸烷-2_酮(trans)_2-side oxygen + oxazazaspiro[4.5]decane-8-carboxylic acid ethyl ester (intermediate I5, 100 mg, 0.440 mmol), 3-iodo_1_ Mercapto-1H-pyrazole (0.088 ml, 0·880 mmol), N,NT-dimercapto-1,2-ethanediamine # (0.014 ml, 0·132 mmol), iodide Copper (1) (25.1 mg, 0.132 mmol) and potassium carbonate (219 mg, 1.584 mmol) were suspended in 1,4-dioxane (4 ml) and the mixture was irradiated with microwave at 130 ° C Heating for 15 30 minutes, then heating at 15 ° C for 30 minutes, in the last cycle, some epimerization is observed (according to UPLC-MS analysis, about 2-3%) The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Drying with sodium sulfate-72-200838508, filtering, concentration, and the residue was chromatographed on silica gel, and the mixture was separated by cyclohexane/ethyl s-S-S 9/1 to 3/7. Ethyl acetate was dissolved at 1/1 'collected 1 08 mg of the title compound. H NMR (400 MHz, CDC13): δ 7.29 (1H, d), 6.64 (1H, 5 d)? 4.16 (2H? qua)5 3.86 (2H9 s)5 3.83 (3H5 s)? 2.47 (1H, sept) , 2·04-2·15 (2H, m), 1.92-2.01 (2H, m), 1.87 (2H, td), 1·68-1·81 (2H, m), 1·28 (3H, t ); UPLC_MS: 0.63 minutes, 308 [M+H]+ 〇JO Intermediate 22 L Α·)-8_(Thrylmethyl)_3·(1_甲某-iH-p比峻) Small gas nitrogen Heterospiral [4.51 decane-2-ketone]
將(反式)-3-(1-甲基-1H-吡唑-3-基)-2-側氧_1_氧雜_3_ 15 氮雜螺[4·5]癸烷-8-羧酸乙酯(中間物20及中間物21,284 毫克,0.924毫莫耳)溶解於四氫呋喃(6.6毫升),冷卻至 -78°C,其間滴入氳化鋁鋰(〇·924毫升,0.924毫莫耳),令 混合物回溫至-40°C,並在此溫度下攪拌1小時,加入硫 酸鈉見水劑將反應中止,加入二乙醚,攪拌2小時後,將 -73- 200838508 懸浮液過濾,殘留物經二氯曱烷洗滌(3x20毫升),濾液被 濃縮後,粗製品於矽膠上被層析,以97/3至9/1的二氯曱 烷/曱醇溶離,收集得235毫克的標題化合物。 NMR (400 MHz5 CDC13): δ 7.29 (1Η5 d)5 6.66 (1Η5 5 d),3·87 (2Η,s),3·83 (3Η,s)5 3·52 (2Η,d), 1.89-2.04 (4Η, m),1·84 (2Η,td),1·54-1·67 (1Η,m),1·41 (1Η,brs),1·18 (2Η,quad); UPLOMS: 0·48 分鐘,266 [Μ+Η]+。(trans)-3-(1-methyl-1H-pyrazol-3-yl)-2-oxooxy-1_oxa-3_ 15 azaspiro[4·5]decane-8-carboxylate Ethyl acetate (intermediate 20 and intermediate 21, 284 mg, 0.924 mmol) was dissolved in tetrahydrofuran (6.6 ml), cooled to -78 ° C, and lithium aluminum hydride was added dropwise (〇·924 ml, 0.924 m). Mohr), the mixture was warmed to -40 ° C, and stirred at this temperature for 1 hour, the reaction was stopped by adding sodium sulfate to the aqueous solution, diethyl ether was added, and after stirring for 2 hours, the suspension of -73-200838508 was filtered. The residue was washed with dichloromethane (3×20 mL). After the filtrate was concentrated, the crude product was chromatographed on silica gel and eluted with 97/3 to 9/1 of dichloromethane/nonyl alcohol to obtain 235 mg. The title compound. NMR (400 MHz5 CDC13): δ 7.29 (1Η5 d)5 6.66 (1Η5 5 d),3·87 (2Η,s),3·83 (3Η,s)5 3·52 (2Η,d), 1.89- 2.04 (4Η, m),1·84 (2Η,td),1·54-1·67 (1Η,m),1·41 (1Η,brs),1·18 (2Η,quad); UPLOMS: 0 · 48 minutes, 266 [Μ+Η]+.
Λ0 中間物23 (反式)-3-(1-甲某-1Η-吡唑-3_某V2-侧氣-1-氣雜-3-氮雜嫘 Γ4.51癸烷-8-甲醛Λ0 intermediate 23 (trans)-3-(1-methyl-1 Η-pyrazole-3_V22-side gas-1-gasa-3-azaindole Γ4.51 decane-8-formaldehyde
15 將(反式)-8-(經基曱基)-3-(1-曱基比ϋ坐-3-基)-1-乳 雜-3-氮雜螺[4.5]癸烷-2-酮(中間物22, 230毫克,0.867毫 莫耳)溶解於二氯曱烷(9.0毫升)並以冰浴冷卻著,加入 Dess-Martin過蛾烧(441毫克,1.040毫莫耳),將混合物攪 拌2小時並回溫至15°C,添加二氯曱烷(7〇毫升)並以飽和 的碳酸氫鈉水溶液(25毫升)及鹽水(25毫升)洗滌,有機層 通過一種疏水性之PTFE燒結物,濃縮,粗製品溶解入二 氯曱烷,過濾除去不溶的粒子,將濾液濃縮,製得油質物, -74- 20 200838508 在矽膠上層析,以5/1之二氯曱烷/乙酸乙酯溶離,收集得 183毫克的標題化合物。 !H NMR (400 MHz? CDC13) δ 9.73 (1Π? s)5 7.29 (ΙΠ5 d)5 6·64 (1Η,d),3·82 (3Η,s),3·80 (2Η,s),3·52 (2Η,d), 5 2·42-2·51 (1Η,m),2·08_2·19 (2Η,m)5 1·88-1·98 (2Η,m), 1.73-1 ·88 (4H,m); UPLC-MS: 0·54 分鐘,264 [M+H]+。 中間物24 • (反式)-2-侧氣-3-(2-吡啶基)-1-氣雜-3-氮雜螺「4.51癸烷-8- -10 羧酸乙酯15 (trans)-8-(via fluorenyl)-3-(1-indolylpyridin-3-yl)-1-oxaza-3-azaspiro[4.5]decane-2- The ketone (intermediate 22, 230 mg, 0.867 mmol) was dissolved in dichloromethane (9.0 mL) and cooled in ice bath. Stir for 2 hours and warm to 15 ° C, add dichloromethane (7 mL) and wash with saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). , concentrated, the crude product is dissolved in dichloromethane, filtered to remove insoluble particles, and the filtrate is concentrated to obtain an oily substance, -74- 20 200838508, chromatographed on silica gel to 5/1 dichloromethane/acetic acid The ethyl ester was dissolved and 183 mg of the title compound was collected. !H NMR (400 MHz? CDC13) δ 9.73 (1Π? s)5 7.29 (ΙΠ5 d)5 6·64 (1Η,d),3·82 (3Η,s),3·80 (2Η,s), 3·52 (2Η,d), 5 2·42-2·51 (1Η,m),2·08_2·19 (2Η,m)5 1·88-1·98 (2Η,m), 1.73-1 · 88 (4H, m); UPLC-MS: 0·54 minutes, 264 [M+H]+. Intermediate 24 • (trans)-2-side gas-3-(2-pyridyl)-1-oxa-3-azaspiro"4.51 decane-8- -10 carboxylic acid ethyl ester
將(反式)-2-侧氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-羧酸乙 φ 酯(以類似於中間物15之方式被製備,700毫克,3.08毫莫 耳)溶解於7毫升的曱苯後,加入2-碘吡啶(1263毫克,6.16 15 毫莫耳)、碘化亞銅(1)(29.3毫克,0J54毫莫耳)、(+/-)·反 式-1,2-二胺基環己烷(0.037毫升,0.308莫耳)及碳酸铯 (2509毫克,7.70毫莫耳),在80°C下將混合物加熱,於密 封的管内、氮氣層下,激烈攪拌18小時,混合物被冷卻 至室溫後,置於水(70毫升)與乙酸乙酯(2x00毫升)間分 2〇 配,合併有機層,洗滌(稀鹽酸、水),經Na2S04乾燥,過 -75- 200838508 濾、’在真空下乾無’粗製品以SP1秒膠管柱純化,以環己 烷/乙酸乙酯(93··7至50··50梯度)溶離,製得標題化合物 (823·7毫克,97%收量)。 4 NMR (500 MHz,CDC13) δ 8·33 (1Η,d),8·25 (1Η,d), 5 7.68-74 (1H,m),7·04 (IH,dd)5 4·16 (2H,q)5 4·03 (2H,s), 2·44·2·52 (1H,m),2.04-2.15 (2H,m),1·94-2·02 (2H,m), 1·84-1·92 (2H,m),1.72-1,83 (2H,m),1·28 (3H,t); ^ UPLC-MS: 0·74 分鐘,305[M+H]+ -i〇 中間物25 尽式)-8-(經基曱基)-3-(2-°比咬基)-1-氳雜-3 -氡雜螺『451吞 烷-2-酮(trans)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylic acid ethyl acrylate (prepared in a manner similar to intermediate 15, 700 mg, 3.08 After immersing in 7 ml of toluene, add 2-iodopyridine (1263 mg, 6.16 15 mmol), cuprous iodide (1) (29.3 mg, 0J54 mmol), (+/- · trans-1,2-diaminocyclohexane (0.037 ml, 0.308 mol) and cesium carbonate (2509 mg, 7.70 mmol), the mixture was heated at 80 ° C in a sealed tube, Under a nitrogen blanket, the mixture was stirred vigorously for 18 hours. After the mixture was cooled to room temperature, it was placed between water (70 ml) and ethyl acetate (2×00 ml), and the organic layer was combined and washed (diluted hydrochloric acid, water). It was dried over Na2SO4, filtered through -75-200838508, and dried under vacuum. The crude product was purified by SP1 s s s s s s s s s s s s s s s s s s s s The title compound was obtained (823·7 mg, 97% yield). 4 NMR (500 MHz, CDC13) δ 8·33 (1Η, d), 8·25 (1Η, d), 5 7.68-74 (1H, m), 7·04 (IH, dd) 5 4·16 ( 2H,q)5 4·03 (2H,s), 2·44·2·52 (1H,m),2.04-2.15 (2H,m),1·94-2·02 (2H,m), 1 ·84-1·92 (2H,m), 1.72-1,83 (2H,m),1·28 (3H,t); ^ UPLC-MS: 0·74 minutes, 305[M+H]+ - i〇Intermediate 25 尽)-8-(via thiol)-3-(2-° ratio 咬)-1-氲-3 - 氡 『 "451 吞 -2- -2- ketone
此標題化合物係以類似於製備中間物22之方式势 備’使用(反式)-2-侧氧比咬基)_1_氧雜_3_氮雜螺[4 5] 癸烷-8-羧酸乙酯(中間物24, 820毫克,2.69毫莫耳),製得 標題化合物(416.8毫克,59%收量)。 " NMR (400 MHz,氯仿,·· δ 8.29-8.25 (1H,m),8 20 (1H,td),7·66 (1H,td),7·01-6·97 (1H,m)5 4·00-3·98 (2H m) 3·48 -3·43 (2H,m),2.48-2.43 (1H,m),1·99-1·86 (4H,m) 1.84-1.73 (2H,m),1·61-1·50 (1H,m),1·1〇9]·〇9 (2H,m)。 -76- 200838508 中間物26This title compound is in a manner similar to the preparation of intermediate 22, using 'trans (trans)-2-side oxygen ratio bite)_1_oxa-3-azaspiro[4 5]decane-8-carboxylate Ethyl ester (Intermediate 24, 820 mg, 2.69 mmol) afforded the title compound (416.8 mg, 59% yield). " NMR (400 MHz, chloroform, ·· δ 8.29-8.25 (1H, m), 8 20 (1H, td), 7.66 (1H, td), 7·01-6·97 (1H, m) 5 4·00-3·98 (2H m) 3·48 -3·43 (2H,m), 2.48-2.43 (1H,m),1·99-1·86 (4H,m) 1.84-1.73 ( 2H,m),1·61-1·50 (1H,m),1·1〇9]·〇9 (2H,m). -76- 200838508 Intermediate 26
φ 將(反式)冬(羥基甲基)-3-(2-吡啶基)-1-氧雜-3_氮雜螺 [4.5]癸烷-2-酮(中間物25, 252毫克,0·961毫莫耳)溶解於 45毫升的DCM後,相繼地加入ΤΡΑΡ(42·9毫克,〇·122毫 莫耳)及ΝΜΟ(169毫克,ΐ·φ|1毫莫耳),在室溫下授拌, 直到以TLC監測(Cy: AcOEt 1:1,Rf= 0·49)至起始材料完 10 全消失,添加10毫升的DCM,經由矽藻土過濾,袓夢$ 置於含SP1之Biotage 12M矽膠管柱純化,以環己烧 /AcOEt 1:1溶離,製得標題化合物(133.7毫克,〜54%收量)t 馨 4 NMR (400 MHz,CDC13) δ 9.72 (1H,s),8·33·8 27 (1Η,m),8.23 (1Η,td),7·73-7·67 (1Η,m) 7·06-7·〇〇 (1Ή m) 15 3·96 (2H,s),2·51-2·43 (1H,m),2.18-2.08 (2H,m)’ 1·97_1·72 (6H,m)。 ’ 或者,中間物26可以類似於製備中間物7之方式被 製備,以(反式)-8-(羥基曱基)-3-(2-吼啶基)-1-氧雜_3•氮雜 螺[4.5]癸烷-2-酮(中間物25)替代(反式)_8-(羥基甲基)_3_ 20 笨基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮而得。 •77- 200838508 中間物27 (反式基)-2-侧氧小氡雜Hi·雜螺普烷_8_ 羧酸乙酯Φ (trans) winter (hydroxymethyl)-3-(2-pyridyl)-1-oxa-3-azaspiro[4.5]nonan-2-one (intermediate 25, 252 mg, 0 · 961 millimolar) After dissolving in 45 ml of DCM, ΤΡΑΡ (42·9 mg, 〇·122 mmol) and ΝΜΟ (169 mg, ΐ·φ|1 mmol) were added successively at room temperature. The mixture was mixed until TLC was monitored by TLC (Cy: AcOEt 1:1, Rf = 0·49) until the end of the material disappeared. 10 ml of DCM was added, filtered through diatomaceous earth, and the nightmare was placed in SP1. Purification of the Biotage 12M cartridge, hexanes / EtOAc / EtOAc (EtOAc) ,8·33·8 27 (1Η,m),8.23 (1Η,td),7·73-7·67 (1Η,m) 7·06-7·〇〇(1Ή m) 15 3·96 (2H , s), 2·51-2·43 (1H, m), 2.18-2.08 (2H, m) '1·97_1·72 (6H, m). Alternatively, intermediate 26 can be prepared analogously to the preparation of intermediate 7 to (trans)-8-(hydroxyindenyl)-3-(2-acridinyl)-1-oxa-3. Heterospiro[4.5]decane-2-one (intermediate 25) replaces (trans)_8-(hydroxymethyl)_3_ 20 stupyl-1-oxa-3-azaspiro[4.5]decane-2 - ketones. •77- 200838508 Intermediate 27 (trans)-2- side oxygen small doping Hi·heteroprolane_8_ ethyl carboxylate
將一種6·2··1之反式-及順式-2-侧氧-1-氧雜-3-氮雜螺 [4·5]癸烧-8-叛酸乙酯的混合物(以類似於製備中間物μ 及16的方式被製備,1.2克,5·28毫莫耳)溶解於12·5毫升 的甲本後’加入1-濱-4-氟苯(0.924克,5.28毫莫耳)、破化 亞鋼(1)(0.050克,〇·264毫莫耳)、(仏)_反式],2-二胺基環 己垸(0·〇63毫升,〇·528毫莫耳)及碳酸鉋(3·44克,10 56毫 莫耳)’以微波照射,在150。〇下加熱30分鐘,再加入一 些1-溴·4-氟苯(0.380毫升)、破化亞銅⑴(46毫克)、(+/+ 反式],2-二胺基環己烷(〇·〇42毫升)及碳酸铯(884毫克), 將混合物進行另3循環的微波照射(15〇。〇, 30分鐘),將反 應物倒入水中(50毫升)並以AcOEt萃取(2x80毫升),有機 層以HC1 1M (50毫升)洗滌後,以Na2S04乾燥並在真空下 濃縮,粗製品在矽膠Flash 25M管柱上以Bi〇tage SP1純 化’管柱以環己烧/AcOEt,自80:20至純AcOEt溶離,製 得標題化合物,為與其順式_異構物(173.4毫克)之混合 物,此混合物在一種12M的矽膠管柱内被純化,使用a mixture of 6·2··1 trans- and cis-2-oxo-1-oxa-3-azaspiro[4·5]pyrrol-8-retamate ethyl ester (similar to Prepared in the preparation of intermediates μ and 16 in a manner of 1.2 g, 5.28 mmoles dissolved in 12·5 ml of the base after adding 'bina-4-fluorobenzene (0.924 g, 5.28 mmol) ), broken steel (1) (0.050 g, 〇 · 264 mmol), (仏) _ trans], 2-diaminocyclohexane (0 · 〇 63 ml, 〇 · 528 mmol ) and carbonic acid planer (3. 44 grams, 10 56 millimoles) 'with microwave irradiation, at 150. Heat under the arm for 30 minutes, then add some 1-bromo-4-fluorobenzene (0.380 ml), copper (1) (46 mg), (+/+ trans), 2-diaminocyclohexane (〇) · 〇 42 ml) and cesium carbonate (884 mg), the mixture was subjected to another 3 cycles of microwave irradiation (15 Torr. 〇, 30 minutes), the reaction was poured into water (50 ml) and extracted with AcOEt (2 x 80 ml) The organic layer was washed with HCl 1 M (50 mL), dried over Na 2 SO 4 and concentrated under vacuum, and the crude product was purified on a silica gel Flash 25M column with Bi〇tage SP1. The column was hexane/AcOEt from 80: The title compound was obtained as a mixture of cis-isomers (173.4 mg), which was purified in a 12M silica gel column.
-78· 200838508-78· 200838508
Biotage SP1 並以環己烷/AcOEt 溶離(TLC 7:3, Rf= 〇.4〇), 製得標題化合物(104毫克,60%收量)。 lU NMR (400 MHz5 CDC13) δ 1.22-129 (t5 3Η) L69-1.80 (m,2Η) 1·81-1·99 (m,42Η) 2·03-2·14 (in,2Η) 2.45-2.54 (m5 1Η) 3.72-3.72 (m5 2Η) 4.10-4.18 (m5 2Η) 7·01-7·08 (m,2Η) 7·45-7·52 (m,2H); UPLC-MS: 〇·78 分鐘 322 [Μ+Η]+。 ’ 零 中間物28 10 氟苯基)-8-(羥基甲某VI-氣雜冬氮雜 烷-2-酮 、The title compound (104 mg, 60% yield) was obtained from EtOAc (EtOAc: EtOAc) lU NMR (400 MHz5 CDC13) δ 1.22-129 (t5 3Η) L69-1.80 (m, 2Η) 1·81-1·99 (m, 42Η) 2·03-2·14 (in, 2Η) 2.45-2.54 (m5 1Η) 3.72-3.72 (m5 2Η) 4.10-4.18 (m5 2Η) 7·01-7·08 (m, 2Η) 7·45-7·52 (m, 2H); UPLC-MS: 〇·78 Minutes 322 [Μ+Η]+. 'zero intermediate 28 10 fluorophenyl)-8-(hydroxymethyl-VI-aza-heteroaza-2-one,
將(反式)_3-(4_氟苯基)-2-側氧-1-氧雜-3-氮雜螺[4·5] 癸烧-8-羧酸乙酯(中間物27, 104毫克,0.324毫莫耳)溶解 15 於10毫升的乾燥THF後,冷卻至-78Χ,在此溫度、氮氣 層下,滴入LiAlH4(1.0M,0.324毫升,0.324毫莫耳),以乙 醚稀釋後,加入15克的Na2S04el〇H20,在室溫下反應, 濾下鹽類,以乙醚洗)’真空下將有機層濃縮,製得93毫 克的粗製標題化合物,未再精製下被使用。 20 NMR (400 MHz? CDC13) δ 1.13-1.23 (m? 1H) -79- 200838508 1·56-1·66 (m,1Η) 1·67·1·73 (m,2H) 1·75-1·89 (m,2H) 1.92-2.04 (m5 3H) 3,54 (d5 2H) 3.67-3.72 (m5 1H) 3.76-3.79 (m,2H) 7.04-7.10 (m,2H) 7·49_7·55 (m5 2H)。 5 中間物29 (反式氟茉基)-2-氣雜-3-氮雜螺[4.51癸烷-8-甲醛(trans)_3-(4-fluorophenyl)-2-oxo-1-oxa-3-azaspiro[4·5] oxime-8-carboxylic acid ethyl ester (intermediate 27, 104 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction mixture was stirred at rt. EtOAc (m.) 20 NMR (400 MHz? CDC13) δ 1.13-1.23 (m? 1H) -79- 200838508 1·56-1·66 (m,1Η) 1·67·1·73 (m,2H) 1·75-1 ·89 (m,2H) 1.92-2.04 (m5 3H) 3,54 (d5 2H) 3.67-3.72 (m5 1H) 3.76-3.79 (m,2H) 7.04-7.10 (m,2H) 7·49_7·55 ( M5 2H). 5 Intermediate 29 (trans-fluoromethyl)-2-aza-3-azaspiro[4.51 decane-8-formaldehyde
% 此標題化合物以類似於製備中間物7的方式被製備, 1〇 使用(反式)-3-(4_氟苯基)-8-(羥基曱基)-1-氧雜-3-氮雜螺 [4·5]癸烷-2-酮(中間物28, 93毫克,0.333毫莫耳),製得標 題化合物(35.8毫克,37%收量)。 • lR NMR (400 MHz, CDC13) δ 1.74-1 ·90 (m,4Η) 1.90-2.02 (m5 2Η) 2.08-2.27 (m? 2H) 2.47-2.58 (m, 1Π) 3.69 is (s,2H) 7·08 (t5 2H) 7·48-7·52 (dd,2H) 9·75 (s,1H); UPLC-MS: 0·68 分鐘,278 [M+Hf。 中間物30 (反式)-3-(2-氟笨基V2-侧氣-1-氣雜-3-氮雜螺『4.51癸烷-8- 20 羧酸乙酯 -80 - 200838508% This title compound was prepared in a similar manner to the preparation of intermediate 7, using (trans)-3-(4-fluorophenyl)-8-(hydroxyindolyl)-1-oxa-3-nitro Heterospiro[4·5]nonan-2-one (Intermediate 28, 93 mg, 0.333 mmol) gave the title compound (35.8 mg, 37% yield). • lR NMR (400 MHz, CDC13) δ 1.74-1 ·90 (m,4Η) 1.90-2.02 (m5 2Η) 2.08-2.27 (m? 2H) 2.47-2.58 (m, 1Π) 3.69 is (s,2H) 7·08 (t5 2H) 7·48-7·52 (dd, 2H) 9·75 (s, 1H); UPLC-MS: 0·68 minutes, 278 [M+Hf. Intermediate 30 (trans)-3-(2-fluorophenyl)V2-side gas-1-gasa-3-azaspiro"4.51 decane-8- 20 carboxylic acid ethyl ester -80 - 200838508
在一密封的反應管内(miniblock XT 12 position),對溶 解於無水的二噚烷(15毫升)之1-氟-2-碘苯及(反式)_2_侧 氧小氧雜1氮雜螺[4·5]癸烷I羧酸乙酯(以類似於製備 中間物15的方式被製備,i克,4·4〇毫莫耳)溶液,加入 Cul(42毫克,〇·22〇毫莫耳)、反式·環己烷二胺(5〇毫克, 0·440耄莫耳)及Κ3Ρ〇4(1·868克,8.80毫莫耳),在氣層下 中、115°C下被加熱1小時,再繼續攪拌3〇分鐘,加入另 外的試劑(Cul、反式-環己烷二胺、1_氟_2_碘苯,各〇.5當 夏),再加熱1小時,以乙酸乙酯稀釋,水洗後,有機層 再以EtOAc萃取,合併有機層,乾燥(Na2S〇4),過濾,減 壓下濃縮,所得殘留物藉由石夕膠層析法純化(4〇M+管柱, 溶離液為Cy-EtOAc 75:25),製得標題化合物,為一種淺 黃色油質物(1.16克)。 NMR (400 MHz? CDC13) δ 1.29 (t5 3Η) 1.70-1.83 (m5 2H) L89-2.05 (m5 4H) 2.05-2.19 (m? 2H) 2.48-2.57 (m? 1H) 3.81 (s5 2H) 4.17 (q? 2H) 7.11-7.32 (m5 3H) 7.56 (td5 1H); UPLC-MS: 0.73 分鐘,322 [M+H]+ 〇 中間物31 -81 - 200838508 ί反式KM2-氟苯基)-8-(羥基甲基VI-氣雜-3-氮雜螺[4.51癸 烷-2-酮In a sealed reaction tube (miniblock XT 12 position), 1-fluoro-2-iodobenzene and (trans)_2_ side oxygen small oxygen 1 aza snail dissolved in anhydrous dioxane (15 ml) [4·5] decane Icarboxylic acid ethyl ester (prepared in a manner similar to the preparation of intermediate 15, i g, 4·4 mM millimolar) solution, added Cul (42 mg, 〇·22〇 mmol) Ear), trans-cyclohexanediamine (5 〇 mg, 0·440 耄mol) and Κ3Ρ〇4 (1·868 g, 8.80 mmol), under the gas layer, at 115 ° C Heat for 1 hour, continue stirring for 3 minutes, add additional reagents (Cul, trans-cyclohexanediamine, 1-fluoro-2-iodobenzene, each 〇.5 for summer), and heat for another hour. Diluted with EtOAc, EtOAc (EtOAc)EtOAc.EtOAc. The title compound was obtained as a pale yellow oil (1.16 g). NMR (400 MHz? CDC13) δ 1.29 (t5 3Η) 1.70-1.83 (m5 2H) L89-2.05 (m5 4H) 2.05-2.19 (m? 2H) 2.48-2.57 (m? 1H) 3.81 (s5 2H) 4.17 ( q? 2H) 7.11-7.32 (m5 3H) 7.56 (td5 1H); UPLC-MS: 0.73 min, 322 [M+H]+ 〇 intermediate 31 -81 - 200838508 ί trans KM2-fluorophenyl)-8 -(Hydroxymethyl VI-aza-3-azaspiro[4.51 decane-2-one
5 此標題化合物以類似於製備中間物22的方式被製 P 備,使用(反式)-3-(2-氟苯基)-2-侧氧-1 -氧雜-3-氮雜螺[4.5] 癸烷-8-羧酸乙酯(中間物30, 300毫克,0.934毫莫耳),製 得標題化合物(216毫克,83%收量)。 !H NMR (400 MHz, CDC13) δ 1·03-1·18 (m,2Η) ίο 1.52-1.66 (m5 1Η) 1.78-1.98 (m? 5H) 1.99-2.10 (m5 2H) 3.48 (d,2H) 3.80 (s,2H) 7.08-7.29 (m,3H) 7·53 (td,1H); UPLC-MS: 0·57 分鐘,280 [M+H]+。 , 中間物32 15 (反式)-3-(2-氟茉基)-2-侧氣_1-氣雜-3-氮雜嫘「4.51癸烷-8- 曱醛5 This title compound was prepared in a manner similar to the preparation of intermediate 22 using (trans)-3-(2-fluorophenyl)-2-oxooxy-1 -oxa-3-azaspiro[ The title compound (216 mg, 83% yield). !H NMR (400 MHz, CDC13) δ 1·03-1·18 (m, 2Η) ίο 1.52-1.66 (m5 1Η) 1.78-1.98 (m? 5H) 1.99-2.10 (m5 2H) 3.48 (d, 2H 3.80 (s, 2H) 7.08-7.29 (m, 3H) 7·53 (td, 1H); UPLC-MS: 0·57 minutes, 280 [M+H]+. , intermediate 32 15 (trans)-3-(2-fluoromethyl)-2-side gas _1-gas-3-azaindole "4.51 decane-8-furfural
-82- C S ) 200838508 此標題化合物以類似於製備中間物7的方式被製備, 使用(反式)-H2_氟苯基冰(經基甲基)小氧雜i氮雜螺 [4.5]癸烷-2-酮(中間物31,216毫克,〇·773毫莫耳),未經 過層析純化步驟,製得標題化合物(15〇毫克,7〇%收量)了 lR NMR (400 MHz5 CDC13) δ 1.77-1.92 (m5 4Η) 1·96-2·08 (m,2Η) 2·1〇-2·23 (m,2Η) 2.47-2.57 (m,1Η) 3·75 (s,2H) 7.12-7.32 (m,3H) 7·55 (td,1H) 9.75 (s,1H);-82-CS ) 200838508 This title compound was prepared in a similar manner to the preparation of intermediate 7 using (trans)-H2_fluorophenyl ice (methicylmethyl) oxaloazane [4.5] 癸Alkan-2-one (intermediate 31, 216 mg, 773 773 mmol), which was purified by chromatography to give the title compound (15 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; δ 1.77-1.92 (m5 4Η) 1·96-2·08 (m, 2Η) 2·1〇-2·23 (m, 2Η) 2.47-2.57 (m, 1Η) 3·75 (s, 2H) 7.12-7.32 (m,3H) 7·55 (td,1H) 9.75 (s,1H);
15 UPLC-MS: 0.63 分鐘,278 [M+H]+。 中間物33 L良式)-2-侧氧-3-「5-(三氟甲某V3-n比咬基i_i_氣雜_3_氣雜 螺『4.51癸烷-8-羧酸乙酯15 UPLC-MS: 0.63 minutes, 278 [M+H]+. Intermediate 33 L good formula)-2- side oxygen-3-"5-(trifluoromethyl V3-n ratio biting base i_i_gas _3_ gas snail snail 4.51 decane-8-carboxylic acid ethyl ester
此標題化合物以類似於製備中間物20的方式被製 備’將3-姨-1-甲基坐換成3->臭-5·(三氣曱基比咬 (597毫克,2·64毫莫耳),製得標題化合物(213毫克)。 lR NMR (400 MHz? CDC13) δ 8.86 (1H5 d)? 8.67 (1H? d)5 8.42 (1H,t),4.19 (2H,qua),3·84 (2H,s),2·56 (1H,sept), 2·09-2·20 (2H,m),1.89-2.05 (4H,m),1.76-1.88 (2H,m), 1·30 (3H,t); UPLC-MS: 〇·75 分鐘,373 [M+H]+。 -83- 200838508 中間物34 〔反式)-8-(羥基曱基)-345-(三氟甲基)-3-吡啶基Μ-氣雜-3-氮雜螺『4.51癸烷-2-酮)This title compound was prepared in a manner similar to the preparation of intermediate 20 'seat 3-姨-1-methyl to 3-> odor-5·(three gas oxime ratio bite (597 mg, 2.64 m) The title compound (213 mg) was obtained. lR NMR (400 MHz? CDC13) δ 8.86 (1H5 d)? 8.67 (1H?d)5 8.42 (1H, t), 4.19 (2H, qua), 3 ·84 (2H, s), 2·56 (1H, sept), 2·09-2·20 (2H, m), 1.89-2.05 (4H, m), 1.76-1.88 (2H, m), 1· 30 (3H,t); UPLC-MS: 〇·75 min, 373 [M+H]+. -83- 200838508 Intermediate 34 [trans)-8-(hydroxyindenyl)-345-(trifluoromethyl) ))-3-pyridyl hydrazine-gas hetero-3-azaspiro"4.51 decane-2-one)
5 此標題化合物以類似於製備中間物22的方式被製 _ 備,使用(反式)-2-侧氧-3-[5-(三氟曱基)-3-吼啶基]小氧雜 -3-氮雜螺[4.5]癸烷-8-羧酸乙酯(中間物33,190毫克, 0.510毫莫耳),製得標題化合物(147毫克)。 4 NMR (400 MHz,CDC13) δ 8·89 (1H,d),8·67 (1H,d), ίο 8.43 (1Η,t),3.85 (2Η,s),3.59 (2Η,t),1·97-2·08 (4Η,m), 1·86-1·97 (2H, m),1·62-1·73 (1H,m),1·42 (1H,t), 1·17-1·31 (2H,m); UPLC-MS: 0.62 分鐘,331 [M+H]+。 • 中間物35 15 (反式)-2-側氣_3-『5-(三氟甲基)-3-吡啶基1-1-氣雜-3-氮雜 嫘「4.51癸烷-8,曱醛5 This title compound was prepared in a similar manner to the preparation of intermediate 22 using (trans)-2-oxo-3-[5-(trifluoromethyl)-3-acridinyl]oxyxan Ethyl 3-azaspiro[4.5]decane-8-carboxylate (Intermediate 33, 190 mg, 0.510 mmol) 4 NMR (400 MHz, CDC13) δ 8·89 (1H, d), 8.67 (1H, d), ίο 8.43 (1Η, t), 3.85 (2Η, s), 3.59 (2Η, t), 1 ·97-2·08 (4Η,m), 1·86-1·97 (2H, m),1·62-1·73 (1H,m),1·42 (1H,t), 1·17 -1·31 (2H, m); UPLC-MS: 0.62 min, 331 [M+H]+. • Intermediate 35 15 (trans)-2-side gas _3-"5-(trifluoromethyl)-3-pyridyl-1-n-oxa-3-azaindole "4.51 decane-8, Furfural
-84- 200838508 此標題化合物以類似於製備中間物23的方式被製 備’使用(反式)·8·(羥基曱基)-3-[5-(三氟曱基)-3-吼啶 基]小氧雜-3-氮雜螺[4·5]-癸烷-2-酮(中間物34,140毫克, 〇·424毫莫耳),製得標題化合物(108毫克)。 5 4 NMR (400 MHz,CDC13) δ 9·77 (1Η,s),8·85 (1Η, d), 8.67 (1H,d),8·42 (1H,tt)5 3.79 (2H, s),2·57 (1H,quint), 2.12-2.23 (2H,m),1·96_2·05 (2H,m),1·8(Μ·96 (4H,m); • UPLC-MS: 0.68 分鐘,329 [M+H]+。 .10 中間物36 (AAlrl-側氧-3-(2-吡畊基)-1-氣雜-3-氮雜螺「4.51癸烷-8-羧酸乙酯-84- 200838508 This title compound was prepared in a similar manner to the preparation of intermediate 23 'Using (trans)·8·(hydroxyindenyl)-3-[5-(trifluoromethyl)-3-acridinyl Small oxa-3-azaspiro[4.5]-nonane-2-one (Intermediate 34, 140 mg, hexanes 424 mmol) afforded the title compound (108 mg). 5 4 NMR (400 MHz, CDC13) δ 9·77 (1Η, s), 8.85 (1Η, d), 8.67 (1H,d),8·42 (1H,tt)5 3.79 (2H, s) , 2·57 (1H, quint), 2.12-2.23 (2H, m), 1.96_2·05 (2H, m), 1·8 (Μ·96 (4H, m); • UPLC-MS: 0.68 minutes ,329 [M+H]+. .10 Intermediate 36 (AAlrl-Side Oxy-3-(2-pyrylene)-1-aza-3-azaspiro"4.51 decane-8-carboxylic acid B ester
此標題化合物以類似於製備中間物20的方式被製 備’將3-蛾-1-曱基-ΙΗ-吼峻換成2-氯吼σ井(0.236毫升,2.64 毫莫耳),製得標題化合物(345毫克)。 1H-NMR (400 MHz,CDC13) δ 9·60 (1Η,dd),8·34 (1Η, d),8.28 (1Η,dd),4·18 (2Η,qua),3·98 (2Η,s),2·52 (1Η, sept),2·07-2·18 (2Η,m),1·96-2·Ό4 (2Η,m),1·87-1·96 (2Η, m),1·73-1·85 (2Η,m),1·30 (3Η,t); UPLC-MS: 0·66 分鐘, 306 [Μ+Η]+。 •85- 200838508 中間物37 (反式V8-(羥基甲基V3-I2-吡畊基VI-氣雜-3-氮雜螺『4.511癸 烷-2-酮This title compound was prepared in a similar manner to the preparation of the intermediate 20'. The title was obtained by replacing the 3-moth-1-indolyl-indole-anthracene into a 2-chloroindole σ well (0.236 ml, 2.64 mmol). Compound (345 mg). 1H-NMR (400 MHz, CDC13) δ 9·60 (1Η, dd), 8·34 (1Η, d), 8.28 (1Η, dd), 4·18 (2Η, qua), 3·98 (2Η, s),2·52 (1Η, sept), 2·07-2·18 (2Η,m),1·96-2·Ό4 (2Η,m),1·87-1·96 (2Η, m) , 1·73-1·85 (2Η, m), 1·30 (3Η, t); UPLC-MS: 0·66 minutes, 306 [Μ+Η]+. •85- 200838508 Intermediate 37 (trans V8-(hydroxymethyl V3-I2-pyrutyl VI-gas-3-azaspiro-4.511-nonan-2-one)
5 ^ 此標題化合物以類似於製備中間物22的方式被製 備,使用(反式)-2-側氧-3-(2-吼畊基)-1-氧雜-3-氮雜螺[4·5] 癸烷-8-羧酸乙酯(中間物36, 325毫克,1.064毫莫耳),製 得槔題化合物(152毫克)。 ίο lU NMR (400 MHz5 CDC13) δ 9.62 (1Η? dd)5 8.34 (1Η? dd),8·28 (1Η,dd),4.00 (2Η,s),3·55 (2Η,t),1·94-2·08 (4Η, m),L82-1.94 (2Η,m),1·61-1·70 (1Η,m),1.40 (1Η,t), 1.15-1J0 (2Η,m); UPLC-MS: 0·49 分鐘,264 [Μ+Η]+。 is 中間物38 (反式)-2-侧氣-3-(2-吡畊基VI-氣雜-3-氮雜螺『4.51癸烷-8- 曱醛5 ^ This title compound was prepared in a similar manner to the preparation of intermediate 22 using (trans)-2-oxo-3-(2-indole)-1-oxa-3-azaspiro[4 5) Ethyl decane-8-carboxylate (Intermediate 36, 325 mg, 1.064 mmol) afforded the title compound (152 mg). Ίο lU NMR (400 MHz5 CDC13) δ 9.62 (1Η? dd)5 8.34 (1Η? dd),8·28 (1Η,dd),4.00 (2Η,s),3·55 (2Η,t),1· 94-2·08 (4Η, m), L82-1.94 (2Η, m), 1·61-1·70 (1Η, m), 1.40 (1Η, t), 1.15-1J0 (2Η, m); UPLC -MS: 0.49 minutes, 264 [Μ+Η]+. Is intermediate 38 (trans)-2-side gas-3-(2-pyrrolidyl VI-gas hetero-3-azaspiro"4.51 decane-8-furfural
-86- 200838508 此標題化合物以類似於製備中間物23的方式被製 備’使用(反式)|(羥基曱基)·3_(2-吼畊基)小氧雜_3_氮雜 螺[4·5]癸烷冬酮(中間物37, 150毫克,0.570亳莫耳),製 得標題化合物(91亳克)。 ^ 5 lH NMR (400 MHz,CDC13) δ 9·72 (1Η,s),8·60 (1Η,-86- 200838508 This title compound was prepared in a similar manner to the preparation of intermediate 23 'Using (trans)|(hydroxyindenyl)·3_(2-indole) small oxa-3_azaspiro[4 5) decane ketone (intermediate 37, 150 mg, 0.570 mmol) to give the title compound (91 g). ^ 5 lH NMR (400 MHz, CDC13) δ 9·72 (1Η, s), 8.60 (1Η,
dd),8·34 (1Η,d)5 8·28 (1Η,dd),3·92 (2Η,s),2·47_2·55 (1Η, m),2·11-2·22 (2H,m),1·92_2·02 (2H,m),1.79-1.91 (4H m); _ UPLC-MS: 〇·57 分鐘,262 [M+H]+。 ,10 中間物39 H順..式侧氧-3::(3-吡啶基V1-氣雜-3-氮雜螺『4.51恭 羧酸乙酯Dd),8·34 (1Η,d)5 8·28 (1Η,dd),3·92 (2Η,s),2·47_2·55 (1Η, m),2·11-2·22 (2H , m), 1·92_2·02 (2H, m), 1.79-1.91 (4H m); _ UPLC-MS: 〇·57 minutes, 262 [M+H]+. , 10 Intermediate 39 H cis.. Formula Side Oxygen-3::(3-Pyridinyl-V1-gasa-3-azaspiro"4.51 PCT
15 此標題化合物以類似於製備中間物30的方式被製 備,將1-氟-2-碘苯換成3-溴吼啶(250毫克,1·584毫莫耳) 並將(反式)-2-侧氧-1-氧雜_3_氮雜螺[4.5]癸烷-8-羧酸乙酯 換成(順式)-2-侧氧小氧雜-3-氮雜螺[4·5]癸烷-8-羧酸乙酯 (以類似於製備中間物16的方式被製備,300毫克,1·32毫 2〇 莫耳),製得標題化合物(290毫克)。 !H NMR (400 MHz5 CDC13) δ 8.55 (d? 1Η)9 8.40 (dd5 -87- 200838508 1H),8.26 (dq,IH),7.36-7.31 (m,1Η),4·17 (q,2H),3·78 (s, 2H),2.43-2.33 (m,IH),2.22-1.15 (m,8H),1·28 (t,3H); UPLC-MS: 0.53 分鐘,305 []\4+11]+。 5 中間物40 (順式羥基曱基)-3-(3-吡啶基)-1-氣雜-3-氮雜螺「4.51癸 烧-2-嗣15 This title compound was prepared in a similar manner to the preparation of intermediate 30, which was changed from 1-fluoro-2-iodobenzene to 3-bromo acridine (250 mg, 1. 584 mmol) and (trans) Ethyl 2-oxo-1-oxa-3_azaspiro[4.5]decane-8-carboxylate was replaced by (cis)-2-oxooxythiazepine-3-azaspiro[4· 5] Ethyl decane-8-carboxylate (prepared in a manner similar to the preparation of Intermediate 16), mp. !H NMR (400 MHz5 CDC13) δ 8.55 (d? 1Η)9 8.40 (dd5 -87- 200838508 1H), 8.26 (dq, IH), 7.36-7.31 (m, 1Η), 4·17 (q, 2H) ,3·78 (s, 2H),2.43-2.33 (m,IH),2.22-1.15 (m,8H),1·28 (t,3H); UPLC-MS: 0.53 minutes,305 []\4+ 11]+. 5 Intermediate 40 (cis-hydroxyindenyl)-3-(3-pyridyl)-1-aza-3-azaspiro"4.51癸 嗣-2-嗣
1010
15 此標題化合物以類似於製備中間物22的方式被製 備,使用(順式)-2-側氧-3-(3-吼啶基)-1-氧雜-3-氮雜螺[4.5] 癸烷-8-羧酸乙酯(中間物39, 150毫克,0.493毫莫耳),製 得標題化合物(121毫克)。 !H NMR (400 MHz? CDC13) δ 8.56 (d9 1Η)9 8.34 (d, 1Η)5 8·16 (dq,1Η),7.32-7.28 (m,1),3.74 (s,2Η),3·51 (d,2Η), 2·76 (br s,1H),2.21-1.38 (m,9H)· UPLOMS: 0·38 分鐘, 263 [M+H]+ 〇 中間物41 (順式V2-侧氣-3-0-吡啶基氣雜-3-氮雜螺「4.51癸烷-8- 20 曱經 -88 - 20083850815 This title compound was prepared in a similar manner to the preparation of intermediate 22 using (cis)-2-oxo-3-(3-indolyl)-1-oxa-3-azaspiro[4.5] Ethyl decane-8-carboxylate (Intermediate 39, 150 mg, 0.493 mmol) !H NMR (400 MHz? CDC13) δ 8.56 (d9 1Η)9 8.34 (d, 1Η)5 8·16 (dq,1Η),7.32-7.28 (m,1),3.74 (s,2Η),3· 51 (d, 2Η), 2·76 (br s, 1H), 2.21-1.38 (m, 9H)· UPLOMS: 0·38 minutes, 263 [M+H]+ 〇 intermediate 41 (cis V2-side Gas-3-0-pyridyl gas hetero-3-azaspiro"4.51 decane-8- 20 曱-88 - 200838508
此標題化合物以類似於製備中間物23的方式被製 備,使用(順式)-8-(羥基曱基)-3-(3j比啶基)-1-氧雜-3-氮雜 螺[4·5]癸烷-2-酮(中間物40, 121毫克,0.461毫莫耳),製 得標題化合物(110毫克)。This title compound was prepared in a similar manner to the preparation of intermediate 23 using (cis)-8-(hydroxyindolyl)-3-(3j-pyridyl)-1-oxa-3-azaspiro[4 5) decane-2-one (Intermediate 40, 121 mg, 0.461 mmol) afforded the title compound (110 mg).
!H NMR (400 MHz5 CDC13) δ 9.67 (d5 1Π)5 8.55 (d5 1Η)5 8·42 (dd,1Η),8·26 (dq,1Η),7·34 (ddd,1Η),3.80 (s,2Η), 2·38-2·27 (m5 1H)5 2·25-0·81 (m5 8H); UPLCMVIS: 0·40 分鐘, 261 [M+H]+ 〇 10 中間物42 (反式)-2-侧氧-3-(3-吡啶基VI-氣雜-3-氮雜螺「4.51癸烷-8- 羧酸乙酯!H NMR (400 MHz5 CDC13) δ 9.67 (d5 1Π)5 8.55 (d5 1Η)5 8·42 (dd,1Η),8·26 (dq,1Η),7·34 (ddd,1Η), 3.80 ( s,2Η), 2·38-2·27 (m5 1H)5 2·25-0·81 (m5 8H); UPLCMVIS: 0·40 minutes, 261 [M+H]+ 〇10 Intermediate 42 (reverse -2-)oxy-3-(3-pyridyl VI-gas-3-azane "4.51 decane-8-carboxylate"
將3-溴吼啶(209毫克,1.320毫莫耳)、(反式)-2-侧氧 -1 -氧雜-3-氮雜螺[4.5]癸烷-8-羧酸乙酯(以類似於製備中 間物15的方式被製備,300毫克,1.320毫莫耳)、(反式)-二胺基環己烷(15.07毫克,0.132毫莫耳)及1,4-二畤烷(20 -89 - 15 200838508 毫升)被置於可微波的小玻璃瓶(20毫升)内,在微波照射 的150 C下攪:摔30分鐘’再於160°C下攪:摔2小時30分 鐘’反應混合物以DCM(100毫升)淋洗,並經水(2χ2〇毫 升)洗滌,乾燥,真空下濃縮,殘留物以Biotage SP1,經 5 由一種25MKP-NH筒純化,以環己烷/EtOAc進行梯度济 洗,收得呈無色固體之標題化合物(190毫克)。 4 NMR (400 MHz,CDC13) δ 8·61 (dd,1H),8·41 ⑹ 1Η),8·22 (dq,1Η),7.33 (ddd,1Η),4·18 (q,2Η),3 / 癱 1 (s, 響 2H),2.55 (m,1H)5 2.18-1.75 (m? 8H)? 1.29 (t5 3^ JO UPLC-MS: 0.56 m,305 [M+H]+。 ’ 在此反應中也收集到相關的異構物,(順式)_2、匈^ -3-(3-吡啶基)-1-氧雜-3-氮雜螺[4·5]癸烷-8-羧酸乙醋(中^ 物39),為一種無色固體(120毫克)· " 4 NMR (400 MHz,CDC13) δ 8·55 (d,1Η),8·4〇 (dd 15 1H),8.25 (dq,1H),7.32 (ddd,1H),4·17 (q,2H),(s’ 2H),2.38 (m, 1H),2.21-L93 (m,6H),1·71-1·61 (m 1·28 (t,3H)。 中間物43 2〇 (反式)-8-(經基甲基)-3-(3-吼咬基)-1-氡雜-3-氮_^£^^ 烧-2-酮3-bromo acridine (209 mg, 1.320 mmol), (trans)-2-oxooxy-1 -oxa-3-azaspiro[4.5]decane-8-carboxylic acid ethyl ester Prepared in a manner similar to the preparation of intermediate 15, 300 mg, 1.320 mmol, (trans)-diaminocyclohexane (15.07 mg, 0.132 mmol) and 1,4-dioxane (20) -89 - 15 200838508 ml) was placed in a microwaveable vial (20 ml) and stirred under microwave irradiation at 150 C: 30 minutes off and then stirred at 160 °C: 2 hours and 30 minutes off. The mixture was rinsed with EtOAc EtOAc EtOAc (EtOAc)EtOAc. The title compound (190 mg) was obtained as a colorless solid. 4 NMR (400 MHz, CDC13) δ 8·61 (dd, 1H), 8·41 (6) 1Η), 8.22 (dq, 1Η), 7.33 (ddd, 1Η), 4·18 (q, 2Η), 3 / 瘫1 (s, ring 2H), 2.55 (m, 1H)5 2.18-1.75 (m? 8H)? 1.29 (t5 3^ JO UPLC-MS: 0.56 m, 305 [M+H]+. The related isomers were also collected in this reaction, (cis)_2, Hungarian-3-(3-pyridyl)-1-oxa-3-azaspiro[4·5]nonane-8- Ethyl acetate (middle 39), a colorless solid (120 mg) · " 4 NMR (400 MHz, CDC13) δ 8·55 (d, 1 Η), 8.4 〇 (dd 15 1H), 8.25 (dq, 1H), 7.32 (ddd, 1H), 4·17 (q, 2H), (s' 2H), 2.38 (m, 1H), 2.21-L93 (m, 6H), 1·71-1 · 61 (m 1 · 28 (t, 3H). Intermediate 43 2 〇 (trans)-8-(ylmethyl)-3-(3-indole)-1-oxa-3-nitrogen _^£^^ Burn-2-one
-90- 200838508 此標題化合物以類似於製備中間物22的方式被製 備’使用(反式)-2-侧氧-3-(3-σ比唆基)小氧雜-3-氮雜螺[4.5] 癸烧-8-叛酸乙酯(以類似於製備中間物42的方式被製備, 1000毫克,3.29毫莫耳),製得標題化合物(600毫克)。 NMR (400 MHz,CDC13): 8.62 (d,1Η),8.41 (dd,1Η), 8·25 (dq,1H),7.34 (ddd,1H),3·84 (s,2H),3.58 (t,2H), 2.07-1.15 (m5 9H); UPLC-MS: 0·38 分鐘,263 [M+H]、 中間物44 侧氡-3_(3-吡啶基M-氣雜-3-氮雜螺「4.51癸^^ 甲醛-90- 200838508 This title compound was prepared in a similar manner to the preparation of intermediate 22 'Using (trans)-2-oxo-3-(3-σ-pyridyl)oxyxan-3-azaspiro[ 4.5] Terpin-8-oleic acid ethyl ester (prepared in a manner similar to the preparation of intermediate 42, 1000 mg, 3.29 mmol) afforded the title compound (600 mg). NMR (400 MHz, CDC13): 8.62 (d, 1 Η), 8.41 (dd, 1 Η), 8·25 (dq, 1H), 7.34 (ddd, 1H), 3·84 (s, 2H), 3.58 (t , 2H), 2.07-1.15 (m5 9H); UPLC-MS: 0·38 min, 263 [M+H], intermediate 44 side 氡-3_(3-pyridyl M-gas-3-azane snail "4.51癸^^ formaldehyde
此標題化合物以類似於製備中間物23的方式被製 備’使用(反式)-8-(羥基曱基)-3-(3-吼啶基)_1_氧雜-3-氮雜 螺[4·5]癸烷-2-酮(中間物43, 100毫克,0.381毫莫耳),製 得標題化合物(5〇毫克)。 4 NMR (400 MHz,CDC13): 9.76 (s,1Η),8.60 (d,1Η) 8 41 (dd,1H),8·21 (dq,1H),7·34 (ddd,1H),3·76 (s,2H), 2.59-2.51 (m,1H),2·22-1·26 (m,8H)。 ±Λ^45This title compound was prepared in a similar manner to the preparation of intermediate 23 ' using (trans)-8-(hydroxyindolyl)-3-(3-acridinyl)-1_oxa-3-azaspiro[4 5 decane-2-one (Intermediate 43, 100 mg, 0.381 mmol) afforded the title compound (5 mg). 4 NMR (400 MHz, CDC13): 9.76 (s, 1 Η), 8.60 (d, 1 Η) 8 41 (dd, 1H), 8·21 (dq, 1H), 7·34 (ddd, 1H), 3· 76 (s, 2H), 2.59-2.51 (m, 1H), 2·22-1·26 (m, 8H). ±Λ^45
-91 - 200838508 1-ί3-氟-2-g比咬基) 將3-氟-2-吡啶甲腈(2克,16·38毫莫耳)溶解於乾燥的 乙醚(6毫升)内並冷卻至,然後滴入溶解於乙醚(12毫 5 升)中之曱基溴化鎂溶液(6·55毫升,19.66毫莫耳),添加 完後,將反應物攪拌16小時並使回溫至室溫,混合物以 φ 1M之HC1水洛液(5〇毫升)中止反應並予以攪拌2小時, 再以—nh4oh水鹼化直至pH 8,水溶液以DCM (3χΐ⑽毫 _ 升)萃取,合併的有機層被乾燥(Na2S04),過濾,濃縮至乾, 10 製得2·1克的粗製品,將其置於矽膠管柱bi〇tage40M上 純化,以10/0至6/4的環己烷/EtOAc混合物溶離,製得 標題化合物(1·4克)。 !H NMR (400 MHz, CDC13) δ 8.52 (dt, 1Η), 7.58-7.49 (m,2H),2.73 (s, 3H); UPLC-MS: 0.47 分鐘,139 [M+H]+。 中間%^ 二(3_氟-2-吼咭基)乙酮-91 - 200838508 1-ί3-Fluoro-2-g ratio bite base 3-Fluoro-2-pyridinecarbonitrile (2 g, 16.38 mmol) dissolved in dry diethyl ether (6 mL) and cooled Then, a solution of decylmagnesium bromide (6.55 ml, 19.66 mmol) dissolved in diethyl ether (12 5 L) was added dropwise. After the addition, the reaction was stirred for 16 hours and allowed to warm to room. The mixture was quenched with φ 1M HCl solution (5 〇 ml) and stirred for 2 hours, then alkalized with -nh4oh water until pH 8. The aqueous solution was extracted with DCM (3 χΐ (10) vol) and combined organic layers. It was dried (Na2SO4), filtered, and concentrated to dryness to give a crude material (1 g, EtOAc, EtOAc EtOAc EtOAc The mixture was dissolved to give the title compound (1·4 g). !H NMR (400 MHz, CDC13) δ 8.52 (dt, 1 Η), 7.58-7.49 (m, 2H), 2.73 (s, 3H); UPLC-MS: 0.47 min, 139 [M+H]+. Intermediate %^ bis(3_fluoro-2-indolyl)ethanone
將氯(三甲基)矽胺烷(1·368毫升,10.78毫莫耳)及三 乙基胺(2.99毫升,21·56毫莫耳)加至溶解於dmF(25亳升) 之1-(3-氟_2•吡啶基)乙酮(中間物衫,丨25〇克,g %毫莫耳) -92· 200838508 之溶液内,在60°C下將混合物搖動23小時,使粗製品回 溫至室溫,藉由Biotage V10汽提除去DMF,殘留物被溶 解於100毫升的DCM内,以冷的NaHC〇3洗滌二遍,收 集有機層,蒸發除去DCM,粗製品被溶解於四氫呋喃 (25.00毫升),加入N-溴琥拍醯亞胺(ι·599克,8.98毫莫 耳)’在0°c下攪拌1小時,再回溫至室溫,攪拌94小時, 減壓下除去THF,粗製品被溶解於DCM,以NaHC〇3洗 滌二遍,有機層被收集後,減壓下濃縮,製得1·7克的粗 製品,藉由矽膠管柱Biotage 401V[純化,以DCM/Et2〇的 混合液(1/0至4/6)溶離,製得標題化合物(490毫克)。 'H NMR (400 MHz5 CDC13) δ 8.54-8.51 (m5 1H) 7·62-7·56 (m,2H),4.76 (s,2H); UPLC-MS: 〇·61 分鐘,218’ 220 [M+H]+ 〇 ’ 15 中間物47 氟吡啶基V k V噻唑-2-胺 將溴-1-(3_氟吡啶基)乙酮(中間物46, 480毫克 2.202耄莫耳)及硫脲(168毫克,22〇2亳莫耳)溶解於乙醇 20 (2〇毫升)並在90它下攪拌2小時,減壓下蒸發除去乙醇' 所得粗製品被溶解於DCM,以NaHC〇3洗滌二遍,將有 機層濃縮,粗製品藉由SCX離子交換筒純化,製得標題 化合物(320毫克,1.639毫莫耳,74.5%收量)。 、 -93- 200838508 4 NMR (400 MHz,CDC13) δ 8·41 (d,1Η),7·73 (dd, 1H),7.44-7.35 (m,1H),7.19 (s,1H),7·14 (s,1H); UPLC-MS: 0.39 分鐘,195 [M+H]、 5 中間物48 (反式)-3-(2-曱基-3-吼啶基)-2-侧氣-1-氣雜-3-氮雜螺『4j] 癸烷-8-羧酸乙酷Chloro(trimethyl) guanamine (1·368 ml, 10.78 mmol) and triethylamine (2.99 ml, 21·56 mmol) were added to dissolve in dmF (25 liters) 1- (3-fluoro-2-pyridyl) ethyl ketone (intermediate shirt, 丨25 gram, g% millimolar) -92·200838508 The solution was shaken at 60 ° C for 23 hours to make the crude product After warming to room temperature, DMF was removed by stripping with Biotage V10, the residue was dissolved in 100 mL of DCM, washed twice with cold NaHC 〇3, organic layer was collected, DCM was evaporated, and the crude product was dissolved in tetrahydrofuran. (25.00 ml), add N-bromonazone (Ig 599 g, 8.98 mmol), stir at 0 °C for 1 hour, then warm to room temperature, stir for 94 hours, remove under reduced pressure THF, the crude product was dissolved in DCM, washed twice with NaHC 〇3, and the organic layer was collected and concentrated under reduced pressure to give a crude product of 1.7 g, by gelatin column Biotage 401V [purified to DCM The mixture of /Et2(R) (1/0 to 4/6) was dissolved to give the title compound (490 mg). 'H NMR (400 MHz5 CDC13) δ 8.54-8.51 (m5 1H) 7·62-7·56 (m, 2H), 4.76 (s, 2H); UPLC-MS: 〇·61 min, 218' 220 [M +H]+ 〇' 15 Intermediate 47 fluoropyridyl V k V thiazol-2-amine bromo-1-(3-fluoropyridyl)ethanone (intermediate 46, 480 mg 2.202 mol) and thiourea (168 mg, 22 〇 2 亳 Mo Er) dissolved in ethanol 20 (2 〇 ml) and stirred at 90 ° for 2 hours, evaporated under reduced pressure to remove ethanol' The crude product obtained was dissolved in DCM and washed with NaHC 〇 3 The title compound (320 mg, 1.639 mmol, 74.5% yield) was obtained from the title compound. , -93- 200838508 4 NMR (400 MHz, CDC13) δ 8·41 (d, 1Η), 7.73 (dd, 1H), 7.44-7.35 (m, 1H), 7.19 (s, 1H), 7· 14 (s,1H); UPLC-MS: 0.39 min, 195 [M+H], 5 intermediate 48 (trans)-3-(2-indolyl-3-acridinyl)-2- side gas- 1-oxa-3-azaspiro-[4j] decane-8-carboxylic acid
10 15 在一種反應瓶(miniblock XT 24 position)内,對溶解於 無水的二噚烷(22毫升)内之3-溴-2-曱基吡啶(1·〇〇9毫升, 8·77毫莫耳)及(反式)-2-侧氧-1-氧雜-3-氮雜螺[4.5]癸烷·8· 羧酸乙酯(以類似於製備中間物15的方式被製備,ι·66克, 7.30毫莫耳)之溶液,加入Cnl(0.070克,〇·365毫莫耳)、 反式-環己烷二胺(〇·〇88毫升,0.730毫莫耳)及尺31>〇4(3.1() 克,Η·61毫莫耳),在氮氣層内,於liyc (外部溫度)下將 混合物加熱4小時,再加入Cul(693毫克,3.65毫莫耳)及 反式-環己烷二胺(0.875毫升,7.30毫莫耳),將外部溫度升 高至130°C(内部溫度T=110°C)並將混合物再授掉2小 日可’在至 >里下擅;掉過仪後加EtOAc稀釋並經水洗務(2x20 毫升),水溶液層再次以乙酸乙酯萃取,合併有機層,以 NaJO4乾燥,過濾,濃縮,製得黃色油質物,藉由一系列 -94- 20 200838508 之層析法純化(4〇M+ NH筒,以環己烷/EtOAc至高達 100%的梯度溶離,接著以25M+ NH管柱,以環己燒/Et〇Ae 至高達50%的梯度溶離,再以25M+ NH筒,以環己燒 /EtOAc至兩達50%的梯度溶離)’合併產物劃分,製得標 題化合物(478毫克)。 'H NMR (400 MHz, CDC13) δ 8.50 (dd? 1Π)5 7.58 (dd, 1H),7·23 (dd,1H), 4·17 (2H,q),3·68 (s,2H),2·56 (s,3H(10 15 3-bromo-2-mercaptopyridine (1·〇〇9 ml, 8.77 mmol) dissolved in anhydrous dioxane (22 ml) in a reaction flask (miniblock XT 24 position) Ear) and (trans)-2-oxo-1-oxa-3-azaspiro[4.5]decane·8·carboxylate (prepared in a manner similar to the preparation of intermediate 15, ι· 66 g, 7.30 mmol), adding Cnl (0.070 g, 〇·365 mmol), trans-cyclohexanediamine (〇·〇88 ml, 0.730 mmol) and ruler 31> 4 (3.1 () g, Η · 61 mmol), the mixture was heated in a nitrogen blanket at liyc (external temperature) for 4 hours, then Cul (693 mg, 3.65 mmol) and trans-ring were added. Hexanediamine (0.875 ml, 7.30 mmol), the external temperature was raised to 130 ° C (internal temperature T = 110 ° C) and the mixture was allowed to be re-delivered for 2 hours. After the instrument was removed, it was diluted with EtOAc and washed with water (2×20 ml). The aqueous layer was extracted again with ethyl acetate. The organic layer was combined, dried over NaJO4, filtered and concentrated to give a yellow oily substance by a series of -94- 20 200838508 Chromatography Purification (4 〇M+ NH cartridge, eluted with cyclohexane/EtOAc to a gradient of up to 100%, followed by 25M+ NH column, cyclohexane/Et〇Ae to a gradient of up to 50%, then 25M+ NH cartridge The title compound (478 mg) was obtained eluted eluted elut elut elut elut elut elut 'H NMR (400 MHz, CDC13) δ 8.50 (dd? 1Π)5 7.58 (dd, 1H), 7·23 (dd, 1H), 4·17 (2H, q), 3·68 (s, 2H) ,2·56 (s,3H(
,10 2·50-2·58 (m,1H),1·92-2·07 (m,4H), 1·71·1·83 (m,2H), 1·28 (t,3H); UPLC-MS: 0.54 分鐘,319 [M+H]+。 ’, 10 2·50-2·58 (m, 1H), 1.92-2·07 (m, 4H), 1·71·1·83 (m, 2H), 1·28 (t, 3H); UPLC-MS: 0.54 min, 319 [M+H]+. ’
15 中間物4915 Intermediate 49
此標題化合物以類似於製備中間物22的方式被製 備,使用(反式)-3-(2-甲基-3-吼啶基)_2_侧氧氧雜 雜螺[4.5]癸烷-8-羧酸乙酯(可根據製備中間物48之方法 製備,180毫克,0.565毫莫耳),製得標題化合物,為一種 無色固體(115亳克)。 ^ NMR (400 MHz, CDC13) δ 8.50 (dd, 1H), 7.58 (dd 1H), 7.22 (dd, 1H), 3.71 (s, 2H), 3.53 (t, 2H), 2.56 (s, 3H)! -95- 20 200838508 2.15-1.38 (m,9H),1·15 (q,2H); UPLC-MS: 0·37 分鐘,277 [M+H]、 中間物50 5 (反式)-3-(2-甲基-3-吡啶基)-2-侧氣-1-氣雜-3-氮雜嫘「4.51 癸烷-8-甲醛This title compound was prepared in a similar manner to the preparation of intermediate 22 using (trans)-3-(2-methyl-3-acridinyl)-2_s. Ethyl carboxylate (prepared by the method of Preparation of Intermediate 48, 180 mg, 0.565 mmol) afforded the title compound as a colourless solid (115 g). ^ NMR (400 MHz, CDC13) δ 8.50 (dd, 1H), 7.58 (dd 1H), 7.22 (dd, 1H), 3.71 (s, 2H), 3.53 (t, 2H), 2.56 (s, 3H)! -95- 20 200838508 2.15-1.38 (m,9H),1·15 (q,2H); UPLC-MS: 0·37 min, 277 [M+H], intermediate 50 5 (trans)-3- (2-methyl-3-pyridyl)-2-side gas-1-gasa-3-azaindole "4.51 decane-8-formaldehyde
1010
此標題化合物以類似於製備中間物23的方式被製 備,使用(反式)-8-(羥基甲基)-3-(2-甲基-3-咐啶基)-1-氧雜 -3-氮雜螺[4·5]癸烷-2-酮(中間物49,115毫克,0.416毫莫 耳),製得標題化合物(110毫克),為無色固體。 lR NMR (400 MHz, DMSO-J6): δ 9.62 (s? 1Η)9 8.41 (dd,1Η),7·80 (dd,1Η),7·30 (dd,1Η),3·76 (s,1Η),2·40 (s, 3H),2.00-1.50 (m,8H); UPLC-MS: 0·41 分鐘,275 [M+Hf。 中間物51 (反式)-2-侧氣-3-(5-嘧啶基)-1-氣雜-3-氮雜螺「4.51癸烷-8-羧酸乙酯 -96- 200838508This title compound was prepared in a similar manner to the preparation of intermediate 23 using (trans)-8-(hydroxymethyl)-3-(2-methyl-3-acridinyl)-1-oxa-3 - azaspiro[4·5]nonan-2-one ( Intermediate 49, 115 mg, 0.416 mmol). lR NMR (400 MHz, DMSO-J6): δ 9.62 (s? 1Η)9 8.41 (dd, 1Η), 7·80 (dd, 1Η), 7·30 (dd, 1Η), 3·76 (s, 1Η), 2·40 (s, 3H), 2.00-1.50 (m, 8H); UPLC-MS: 0·41 minutes, 275 [M+Hf. Intermediate 51 (trans)-2- side gas-3-(5-pyrimidinyl)-1-gasa-3-azaspidine "4.51 decane-8-carboxylic acid ethyl ester -96- 200838508
種75/25的順式/反式2·摘氧小氧雜_3_氮雜螺[4·5] 癸炫I魏乙g旨(以類似於製備中間物15及16的方式被 製備,500^克,2·2〇〇亳莫耳)的化合物、5_漠口密咬(35〇毫 克,2·200晕莫耳)、碘化亞銅(1)(41.9毫克,0.220毫莫耳)、 碟酸1(1401 $克,6·6〇毫莫耳◊、(反式)_二胺基環己烧 (50·2毫克,0.440毫莫耳)被一起放入至一種Car〇usel管, 1075/25 cis/trans 2·oxygenated small oxygen _3_azaspiro[4·5] 癸Hyun I Wei wei g (prepared in a manner similar to the preparation of intermediates 15 and 16, 500^g, 2·2〇〇亳 Mo) compound, 5_ indigenous bite (35〇 mg, 2.200 halo), cuprous iodide (1) (41.9 mg, 0.220 mmol) ), dish acid 1 (1401 $ gram, 6.6 〇 莫 ◊ ◊, (trans) _ diaminocyclohexane (50 · 2 mg, 0.440 mmol) was put together into a Car〇usel Tube, 10
15 然後被懸浮於M-二噚烷(10毫升),所得混合物在stem Block裝置内,於i3(rc下加熱24小時,反應混合物以 DCM(300晕升)淋洗,再以水洗滌(2χ5〇毫升),經分離管 過濾,在真空下將所得的有機層濃縮,製得7〇〇毫克的粗 製品,以Biotage SP1純化,在一種ΚΡ-ΝΗ 40M管柱上, 使用環己烷/EtOAc的梯度溶離,此標題化合物在約3〇% EtOAc時被溶離,為無色固體(no亳克)。 ipi NMR (400 MHz,CDC13) δ 9.01 (s,2H),8.90 (s,1H) 4·04 (q,2Η),3,95 (m5 2Η),2·52-2·35 (m,1Η),2·01-1·83 (m, 4H),1·81-1·66 (m,2H),1.66-1.46 (m,2H),1.17 (t,3H)· UPLC-MS: 0.59 分鐘,306 [M+H]+ 〇 (順式)-2-側氧-3-(5-,咬基)-1-氧雜氮雜螺[4·5]癸 文完-8-竣酸乙S旨在約45% EtOAc下被溶離,也被回收,為 一種無色固體(170毫克)。 -97- 20 200838508 lR NMR (400 MHz, DMSO-i/6): δ 9.03 (s, 2H)9 9.02 (s9 1H),4.18 (q,2H),3.76 (m,2H),2·47-2·35 (m,1H), 2·24-1·94 (m,4H),1.81-1.66 (m,1H),1·78-1·65 (m,2H), 1.29 (t,3H)。 5 UPLC-MS: 0.58 分鐘,306 [M+H]+。 中間物5215 was then suspended in M-dioxane (10 ml) and the resulting mixture was heated in i.sub.3 (rc) for 24 hours. The reaction mixture was rinsed with DCM (300 swell) and washed with water (2 χ5) 〇ml), filtered through a sep. filter, and the obtained organic layer was concentrated in vacuo to yield 7 g of crude product, purified from Biotage SP1 on a ΚΡ-ΝΗ 40M column using cyclohexane/EtOAc The title compound was dissolved in a colorless solid (no gram). mp NMR (400 MHz, CDC13) δ 9.01 (s, 2H), 8.90 (s, 1H) 4· 04 (q, 2Η), 3, 95 (m5 2Η), 2·52-2·35 (m, 1Η), 2·01-1·83 (m, 4H), 1·81-1·66 (m , 2H), 1.66-1.46 (m, 2H), 1.17 (t, 3H) · UPLC-MS: 0.59 min, 306 [M+H]+ 〇(cis)-2- side oxygen-3-(5- , ketone)-1-oxazaspiro[4·5] 癸文完-8- decanoic acid B S is intended to be dissolved in about 45% EtOAc and was also recovered as a colorless solid (170 mg). -97- 20 200838508 lR NMR (400 MHz, DMSO-i/6): δ 9.03 (s, 2H)9 9.02 (s9 1H), 4.18 (q, 2H), 3.76 (m, 2H), 2·47 -2·35 (m,1H), 2·24-1·94 (m,4H),1.81-1.66 (m,1H),1·78-1·65 (m,2H), 1.29 (t,3H 5 UPLC-MS: 0.58 minutes, 306 [M+H]+. Intermediate 52
(反式)-8-(羥基甲基V3-(5-嘧啶基VI-氣雜-3-氮雜螺『4.5Ί癸 烷-2-酮(trans)-8-(hydroxymethyl V3-(5-pyrimidinyl VI-gas-aza-aza-spiro-4.5 oxa-2-one)
1010
15 此標題化合物以類似於製備中間物22的方式被製 備,使用(反式)-2-侧氧-3-(5-嘧啶基)-1-氧雜-3-氮雜螺[4.5] 癸烷-8-羧酸乙酯(中間物51,130毫克,0.426毫莫耳),製 得標題化合物,為一種無色固體(50毫克)。 ιΉ NMR (400 MHz? CDC13) δ 9.05 (s, 2H)? 9.02 (s9 1H)? 3·61 (s,2H),3.59 (t,2H),2.08-1.87 (m,6H),1.71-1.61 (m, 1H),1.30-1.15 (m,2H); Ui>LC-MS: 0.43 分鐘,264 [M+H]+。 中間物53 2〇 (反式V2-侧氣-3-(5-嘧啶基M-氣雜-3-氮雜螺『4.51癸烷-8- 曱醛 -98- 20083850815 This title compound was prepared in a similar manner to the preparation of intermediate 22 using (trans)-2-oxo-3-(5-pyrimidinyl)-1-oxa-3-azaspiro[4.5] Ethyl-8-carboxylate (middle 51, 130 mg, 0.426 mmol) eluted Ή NMR (400 MHz? CDC13) δ 9.05 (s, 2H)? 9.02 (s9 1H)? 3·61 (s, 2H), 3.59 (t, 2H), 2.08-1.87 (m, 6H), 1.71-1.61 (m, 1H), 1.30-1.15 (m, 2H); Ui> LC-MS: 0.43 min, 264 [M+H]+. Intermediate 53 2〇 (trans V2-side gas-3-(5-pyrimidinyl M-gasa-3-azaspiro) 4.51 decane-8-furfural -98- 200838508
此標題化合物以類似於製備中間物23的方式被製 備,使用(反式)-8-(羥基甲基)-3-(5-嘧啶基)-1-氧雜-3-氮雜 5 螺[4.5]癸烷-2-酮(中間物52, 50毫克,0.190毫莫耳),製得 p 標題化合物,為一種無色固體(40毫克)。 NMR (400 MHz? CDC13) δ 9.77 (s9 1Π), 9.03 (s? 1H)? 9.02 (s,2H),3·74 (s,2H),2·57 (quint,1H),2.23-1.80 (m, 8H); PLC-MS: 0.45 分鐘(寬峰),262 [M+H]+。 ίο 中間物54 (順式V2-側氣-3-(2-吡啶基VI-氧雜-3-氮雜螺『4.51癸烷-8- 羧酸乙酯This title compound was prepared in a similar manner to the preparation of intermediate 23 using (trans)-8-(hydroxymethyl)-3-(5-pyrimidinyl)-1-oxa-3-aza 5 snail [ 4.5] decane-2-one (Intermediate 52, 50 mg, 0.190 mmol). NMR (400 MHz? CDC13) δ 9.77 (s9 1Π), 9.03 (s? 1H)? 9.02 (s, 2H), 3.74 (s, 2H), 2·57 (quint, 1H), 2.23-1.80 ( m, 8H); PLC-MS: 0.45 min (wide peak), 262 [M+H]+. Οο Intermediate 54 (cis V2-side gas-3-(2-pyridyl VI-oxa-3-azaspiro) 4.51 decane-8-carboxylic acid ethyl ester
此標題化合物以類似於製備中間物24的方式被製 備,將(反式)-2-側氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-羧酸乙 酯換成(順式)-2-側氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-羧酸乙 -99- 15 200838508 酯且(以類似於製備中間物16的方式被製備,5·71克,251 毫莫耳),製得標題化合物(4.24克)。 H :NMR (400 MHz,CDC13) δ ι·28 (t,3Η) 1·6(Μ·71 (m, 2Η) 1.91-2.08 (m? 4Η) 2.10-2.19 (m? 2H) 2.33-2.44 (m9 1H) 4·17 (q,2H) 7.G4 (dd,1H) 7·68_7·76 (m,1H) 8.26 (d,1H) 8·32 (dd5 1H); UPLC捕·· 〇·71 分鐘,3〇5 [m+h]+。This title compound was prepared in a similar manner to the preparation of intermediate 24, replacing ethyl (trans)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate. (cis)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylic acid ethyl-99- 15 200838508 Ester and (prepared in a manner similar to the preparation of intermediate 16 , 5.71 g, 251 mmol, to give the title compound (4.24 g). H: NMR (400 MHz, CDC13) δ ι·28 (t, 3Η) 1·6 (Μ·71 (m, 2Η) 1.91-2.08 (m? 4Η) 2.10-2.19 (m? 2H) 2.33-2.44 ( M9 1H) 4·17 (q,2H) 7.G4 (dd,1H) 7·68_7·76 (m,1H) 8.26 (d,1H) 8·32 (dd5 1H); UPLC capture·····71 Minutes, 3〇5 [m+h]+.
-10 中間物55 _^_2_制氧比咬基、 巍-3-氮雜嫘『4.51癸烷-8_-10 Intermediate 55 _^_2_ Oxygen ratio biting base, 巍-3-aza 嫘 "4.51 decane-8_
解在™F之(順式)·2、侧氧-3-(2-M基)]-氧雜 方供[45]癸烧叛酸乙黯(可根據製備中間物54之 升去^,地.7毫克,L65亳莫耳)及肌(1取2乃毫 〇·5’小^耄莫耳)之溶液,冷卻至,。C並在此溫度下攪拌 再授#V加人Mel(G·361亳升,5·78毫莫耳),在-78°c下 有機屑、J、日守’將反應混合物倒入水中,以乙醚萃取兩遍, 品,^ Na2s04乾燥,蒸發除去溶劑後,製得一種粗製 離,制」矽膠官柱上純化,以H50%的EtOAc/環己烷溶 例之:传襟題化合物(416·3亳克),為一種以約為70/30比 xx種非鏡像物混合之混合物。 -100. 20 200838508 H-NMR (500 MHz, CDC13) δ 8.32 (1H 主異構物,d), 8·3〇 (1H次異構物,d),㈣(1H主異構物,队8·24’(ιη 次異構物,d),7.67-7.74 (lH主異構物+ 1Η次異構物,m), • 7·00-7·07 (1H 主異構物+ 1H 次異構物,m),415_4·23 (2H Ά 主異構物+2Ή次異構物,m),4.03 (2Η主異構物,s),3·97 (m 次異構物,s),2·27_2·35 (2Η 主異構物,m),m2 i7 (2H次異構物,m),L60_2.02 (4H主異構物+4h次異構 • 物,的,1·38-1·48 (2H主異構物+2h次異構物,m),i、·29 (3H主異構物+3H次異構物,t),1·24 (3H次異構物,s), ίο L23(3H 主異構物,s);UPLC-MS: 1.11,319[Μ+Η]+(主異 構物)及1·13分鐘,319 [Μ+Η]+ (次異構物) 中間物56乃S7 甲基)-8-甲基_3-(2•吡啶某V卜氧雜_3_氮雜Solution in TMF (cis) · 2, side oxygen-3-(2-M-based)]-oxacaine for [45] smoldering sulphuric acid acetamidine (can be raised according to the preparation of intermediate 54 ^, Ground. 7 mg, L65 亳 Mo ear) and muscle (1 take 2 is 〇 〇 · 5 '小 ^ 耄 Mo Er) solution, cooled to,. C and stir at this temperature and then add #V plus Mel (G·361 亳, 5·78 mmol), at -78 °c, the organic chips, J, Rishou 'pour the reaction mixture into the water, After extracting twice with diethyl ether, the product was dried over Na2s04 and evaporated to give a crude residue, which was purified on a silica gel column, eluted with H50% EtOAc/cyclohexane: • 3 gram), a mixture of about 70/30 to xx non-mirror. -100. 20 200838508 H-NMR (500 MHz, CDC13) δ 8.32 (1H main isomer, d), 8·3〇 (1H isomer, d), (iv) (1H main isomer, team 8 · 24' (ιη isomer, d), 7.67-7.74 (lH main isomer + 1 Η isomer, m), • 7·00-7·07 (1H main isomer + 1H difference) Structure, m), 415_4·23 (2H Ά main isomer + 2 异构 isomer, m), 4.03 (2 Η main isomer, s), 3.97 (m isomer, s), 2·27_2·35 (2Η main isomer, m), m2 i7 (2H isomer, m), L60_2.02 (4H main isomer + 4h isomer), 1.38- 1·48 (2H main isomer + 2h isomer, m), i, ·29 (3H main isomer + 3H isomer, t), 1·24 (3H isomer, s ), ίο L23 (3H main isomer, s); UPLC-MS: 1.11,319 [Μ+Η]+ (main isomer) and 1.13 minutes, 319 [Μ+Η]+ (sub-heterogeneous) Intermediate) 56 is S7 methyl)-8-methyl_3-(2•pyridine some V oxa _3_aza
此標題化合物以類似於製備中間物22的方式被製 備’使用8-甲基-2-侧氧-3-(2-°比^定基)-1-氧雜-3-氮雜螺[4·5] 癸烧-8-羧酸乙酯(中間物54, 300毫克,0·942毫莫耳),但 -101- 200838508 允許反應達到室溫再中止反應,製得中間物56 (200毫克, 〇·651毫莫耳,69.1%)及中間物57 (60.4毫克,0.214毫莫 耳,22.73 %) 中間物56 ,5 h-NMR (500 MHz,CDC13) δ 8·32 (1Η,d),8·26 (1Η, d),7·71 (1Η,td),7·03 (1Η,dd),3·99 (2Η,s),3·43 (2Η,d), 1·93-2·01 (2H,m),1·72].81 (4H,m),1·34·1·39 (2H,m), 1·01 (3H,s); 馨 UPLC-MS: 0.84 分鐘,277 [M+Hf 10 中間物57 ^-NMR (500 MHz,CDC13) δ 8·32 (1H,d),8·26 (1H, d),7·72 (1H,td),7.04 (1H,dd),4·01 (2H,s),3.42 (2H,d), 1.92-2.04 (2H,m)5 1.73-1·84 (2H,m),1.47-1.66 (4H,m), 15 1.02 (3H,s): UPLC-MS: 0.82 分鐘,277 [M+H]+ 中間物58 (順式)-8-曱基-2-側氣-3-(2-吡啶基VI-氣雜-3-氮雜螺『4.51 20 癸烷-8-甲醛This title compound was prepared in a similar manner to the preparation of intermediate 22 'Using 8-methyl-2-oxo-3-(2-°-butoxy)-1-oxa-3-azaspiro[4· 5] Ethyl 8-carboxylate (intermediate 54, 300 mg, 0·942 mmol), but -101-200838508 allowed the reaction to reach room temperature and then quenched the reaction to give intermediate 56 (200 mg, 651·651 mmol, 69.1%) and intermediate 57 (60.4 mg, 0.214 mmol, 22.73%) Intermediate 56,5 h-NMR (500 MHz, CDC13) δ 8·32 (1Η,d), 8·26 (1Η, d), 7·71 (1Η, td), 7·03 (1Η, dd), 3·99 (2Η, s), 3·43 (2Η, d), 1·93-2 ·01 (2H,m),1·72].81 (4H,m),1·34·1·39 (2H,m), 1·01 (3H,s); Xin UPLC-MS: 0.84 minutes, 277 [M+Hf 10 Intermediate 57 ^-NMR (500 MHz, CDC13) δ 8·32 (1H, d), 8.26 (1H, d), 7.72 (1H, td), 7.04 (1H, Dd),4·01 (2H,s), 3.42 (2H,d), 1.92-2.04 (2H,m)5 1.73-1·84 (2H,m),1.47-1.66 (4H,m), 15 1.02 (3H,s): UPLC-MS: 0.82 min, 277 [M+H]+ intermediate 58 (cis)-8-mercapto-2- side gas-3-(2-pyridyl VI-gas- 3-azaspiro 20 decane-8-carbaldehyde 4.51
0 -102- 200838508 將(順式)-8-(羥基曱基)_8_甲基_3兴比啶基氧雜 •3-氮雜螺[4.5]癸烷酮(中間物56, 1〇〇毫克,〇·362毫莫 耳)及PLJBX目&胺樹脂懸浮於乾燥的二氯甲烧(1Q毫升) 後,振搖之,反應以UPLC監測且反應非常慢,加入3當 量的PL—IBX醯胺樹脂,5天後在過濾管上過濾並以二氯 甲烷洗滌,有機層在真空下濃縮,製得95毫克的粗製品, 其被置於一種矽膠筒上純化,以環己烷:AcOEt溶離(自30 至100%且以AcOEtMeOH直至50%),製得標題化合物(57 毫克),為一種白色固體。 ^-NMR (400 MHz5 CDC13) δ 9.51 (1Η5 s)? 8.34 (1Η9 d)9 8·27 (1Η,d),7·70-7·77 (1Η,m),7·07 (1Η,dd),4·〇5 (2Η,s), 2.14-2.24 (4H,m),1·92-2·02 (2H,m),1·82-1·91 (2H,m), 1.41-1.51 (2H,m),1·12 (3H,s); UPLC-MS: 0·63 分鐘,275 [M+H]+ 〇 土間物59 式)-8•甲基-2_侧氧-3-(2-°比。定基)-1 -氣雜-3- ft雜螺『4.51 登烷-8-甲醛0-102- 200838508 (cis)-8-(hydroxyindenyl)_8_methyl_3-m-pyridyloxa-3-azaspiro[4.5]nonanone (intermediate 56, 1〇〇) Mg, 〇·362 mmol) and PLJBX mesh & amine resin were suspended in dry methylene chloride (1Q mL), shaken, the reaction was monitored by UPLC and the reaction was very slow, and 3 equivalents of PL-IBX were added. The guanamine resin was filtered on a filter tube after 5 days and washed with dichloromethane. The organic layer was concentrated under vacuum to give a crude product of 95 mg, which was purified on a silica gel cartridge to cyclohexane:AcOEt The title compound (57 mg) was obtained as a white solid. ^-NMR (400 MHz5 CDC13) δ 9.51 (1Η5 s)? 8.34 (1Η9 d)9 8·27 (1Η,d),7·70-7·77 (1Η,m),7·07 (1Η,dd ),4·〇5 (2Η,s), 2.14-2.24 (4H,m),1·92-2·02 (2H,m),1·82-1·91 (2H,m), 1.41-1.51 (2H,m),1·12 (3H,s); UPLC-MS: 0·63 minutes, 275 [M+H]+ 〇土物59 式)-8•methyl-2_side oxygen-3- (2-° ratio. fixed base)-1 - gas hetero-3- ft snail "4.51 dans-8-formaldehyde
此標題化合物以類似於製備中間物23的方式被製 備,使用(反式)-8-(羥基曱基)_8_曱基-3-(2-吡啶基氧雜 •103- < S > 200838508 -3-氮雜螺[4·5]癸烷-2-酮(以類似於製備中間物57的方式 被製備,55毫克,0J99毫莫耳),製得標題化合物(32毫 克),為一種白色固體。 !H-NMR (400 MHz, CDCls) δ 9.48 (1Η? s)5 8,32 (1Π9 dd),8.23 (1Η,d),7·66·7·75 (1Η,m),6.99麵7·08 (1Η,m), 3·92 (2Η,s)5 1·95-2·05 (4Η, m),1·75-1·87 (2Η,m), 1·59-1.71 (2Η,m),1·10 (3Η,s); UPLC-MS: 0·69 分鐘,275 ίο 中間物60 (反式)-3-(6-曱基-2-吡啶基V2-側氣-1-氣雜-3-氮雜嫘『4.51 癸烷-8-羧酸乙酯This title compound was prepared in a similar manner to the preparation of intermediate 23 using (trans)-8-(hydroxyindolyl)-8-mercapto-3-(2-pyridyloxa-103- <S> 200838508 -3-Azaspiro[4·5]nonan-2-one (prepared in a similar manner to the preparation of intermediate 57, 55 mg, EtOAc, EtOAc) A white solid. !H-NMR (400 MHz, CDCls) δ 9.48 (1Η? s) 5 8,32 (1Π9 dd), 8.23 (1Η,d),7·66·7·75 (1Η,m), 6.99 face 7·08 (1Η,m), 3·92 (2Η,s)5 1·95-2·05 (4Η, m),1·75-1·87 (2Η,m), 1·59- 1.71 (2Η,m),1·10 (3Η,s); UPLC-MS: 0·69 minutes, 275 ίο Intermediate 60 (trans)-3-(6-mercapto-2-pyridyl V2-side Gas-1-gas hetero-3-azaindole "4.51 decane-8-carboxylic acid ethyl ester
此標題化合物以類似於製備中間物51的方式被製 15 備,將(順式/反式)-2-側氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-羧 酸乙酯換成(反式)-2-侧氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-羧 酸乙酯(以類似於製備中間物15的方式被製備,904毫克, 3.98毫莫耳)且將5-溴嘧啶換成2-溴-6-曱基吡啶(0.543毫 升,4.77毫莫耳),製得標題化合物,為一種白色固體(222 2〇 毫克,17%)。 巾 NMR (400 MHz,CDC13) δ 1·29(1,3H) 1.73-1 ·94 (m, -104- 200838508 4H) 1.94-2.03 (m,2H) 2· 12 (ddd,2H) 2.45-2.55 (m,4H) 4·03 (s,2H) 4.18 (q5 2H) 6·89 (d,1H) 7.59 (t,1H) 8·〇3 (d 1H); 5 差向異構物,(順式)-3-(6-曱基比啶基)-2-侧氧 氧雜-3-氮雜螺[4·5]癸烷羧酸乙酯也自此反應中被回 收’為一種無色油質物(258毫克,2〇0/〇)。This title compound was prepared in a similar manner to the preparation of intermediate 51, (cis/trans)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate. Ethyl ester was replaced with (trans)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylic acid ethyl ester (prepared in a similar manner to the preparation of intermediate 15) 904 mg, 3.98 mmol, and 5-bromopyrimidine, 2-bromo-6-mercaptopyridine (0.543 ml, 4.77 mmol) to give the title compound as a white solid (222. 17%). Towel NMR (400 MHz, CDC13) δ 1·29 (1,3H) 1.73-1 ·94 (m, -104- 200838508 4H) 1.94-2.03 (m, 2H) 2· 12 (ddd, 2H) 2.45-2.55 (m,4H) 4·03 (s,2H) 4.18 (q5 2H) 6·89 (d,1H) 7.59 (t,1H) 8·〇3 (d 1H); 5 Epimers, (shun Ethyl 3-(6-nonylpyridinyl)-2-oxooxaoxa-3-azaspiro[4·5]nonanecarboxylate is also recovered from this reaction as a colorless oil Quality (258 mg, 2〇0/〇).
!H NMR (400 MHz, CDC13) δ 1.26-1.32 (t5 3Η) 1·54-1·70 (m,2Η) 1·91-2·19 (m,6Η) 2·33-2·43 (m,1Η) 2·48 (s,3H) 3·99 (s,2H) 4.13-4.21 (q,2H) 6·87-6.91 (d,1H) 7·56-7·63 (t,1H) 8·02-8·07 (d,1H)。 中間物61 @式)-8-(羥基甲某V3-(6-甲某-2-吡啶基)-1-氣雜-3-氮雜 螺「4.51癸烷-2-酮!H NMR (400 MHz, CDC13) δ 1.26-1.32 (t5 3Η) 1·54-1·70 (m, 2Η) 1·91-2·19 (m, 6Η) 2·33-2·43 (m ,1Η) 2·48 (s,3H) 3·99 (s,2H) 4.13-4.21 (q,2H) 6·87-6.91 (d,1H) 7·56-7·63 (t,1H) 8 ·02-8·07 (d, 1H). Intermediate 61 @式)-8-(Hydroxymethyl-V3-(6-methyl-2-pyridyl)-1-oxa-3-azaspiro"4.51 decane-2-one
15 此標題化合物以類似於製備中間物22的方式被製 備,使用(反式)-3-(6-甲基-2-吼啶基)-2-侧氧小氧雜-3-氮 雜螺[4.5]癸烷-8-羧酸乙酯(中間物60, 40·6毫克,0·128毫 莫耳),製得標題化合物,為無色油質物(40毫克,0·127毫 莫耳)。 -105- 200838508 4 NMR (400 MHz, CDC13) δ 1.17-1 ·44 (m,4H) 1.55-1.69 (m,1H) 1.91-2.05 (m,4H) 2.49 (s,3H) 3.53-3.60 (t, 2H) 4.03 (s? 2H) 6.85-6.91 (d5 1H) 7.54-7.62 (t5 1H) 8·02-8·07 (d,1H); UPLC-MS: 0·61 分鐘,277 [M+Hf。 中間物6215 This title compound was prepared in a similar manner to the preparation of intermediate 22 using (trans)-3-(6-methyl-2-acridinyl)-2-oxooxyoxa-3-azane. [4.5] Ethyl decane-8-carboxylate (Intermediate 60, 40·6 mg, 0·128 mmol) to give the title compound as a colorless oil (40 mg, 0.127 mmol) . -105- 200838508 4 NMR (400 MHz, CDC13) δ 1.17-1 ·44 (m,4H) 1.55-1.69 (m,1H) 1.91-2.05 (m,4H) 2.49 (s,3H) 3.53-3.60 (t , 2H) 4.03 (s? 2H) 6.85-6.91 (d5 1H) 7.54-7.62 (t5 1H) 8·02-8·07 (d, 1H); UPLC-MS: 0·61 minutes, 277 [M+Hf . Intermediate 62
(反式V346-甲基-2-吡啶基)-2-侧氣-1-氣雜-3-氮雜螺『4.51 癸烷-8-甲醛(trans V346-methyl-2-pyridyl)-2-side gas-1-gas hetero-3-azaspiro"4.51 decane-8-formaldehyde
10 此標題化合物係以類似於製備中間物23之方式製 備,使用(反式)-8-(羥基曱基)-3-(6-曱基-2·-比啶基)-1-氧雜 春 -3-氮雜螺[4.5]癸烷-2-酮(中間物61,36毫克,0.130毫莫 耳),製得此標題化合物(24毫克,67%)。 15 !H-NMR (400 MHz5 CDCI3): δ 1.78-1.96 (m5 6Η) 2.09-2.21 (m5 2H) 2.44-2.53 (m5 4H) 3.98 (s? 2H) 6.89 (d? 1H) 7.60 (t5 1H) 8.03 (d5 1H) 9.76 (s5 1H); UPLC-MS: 0.68 分鐘,275 [M+H]+。 2〇 中間物 63 -106- 200838508 (反式)-3-(6-氟_2_吼唉基>2-側氣-1 _氯雜-3__氮隻翌 烷-8-羧酸乙酯10 This title compound was prepared in a similar manner to the preparation of intermediate 23 using (trans)-8-(hydroxyindolyl)-3-(6-fluorenyl-2·-pyridyl)-1-oxa The title compound (24 mg, 67%) was obtained from EtOAc. 15 !H-NMR (400 MHz5 CDCI3): δ 1.78-1.96 (m5 6Η) 2.09-2.21 (m5 2H) 2.44-2.53 (m5 4H) 3.98 (s? 2H) 6.89 (d? 1H) 7.60 (t5 1H) 8.03 (d5 1H) 9.76 (s5 1H); UPLC-MS: 0.68 minutes, 275 [M+H]+. 2〇Intermediate 63 -106- 200838508 (trans)-3-(6-fluoro_2_mercapto>2-side gas-1 _chloro-3__azepine-8-carboxylic acid B ester
V—NV-N
1010
15 在氮氣層下,將氫化鈉(〇·132克,3·30毫莫耳)攪拌於 乾燥的DMF(10毫升)内,在〇°C下將其慢慢地加入溶解於 乾燥的DMF(10毫升)内之(反式)-2-側氧-1-氧雜_3_氮雜螺 [4·5]癸烷-8-羧酸乙酯(以類似於製備中間物15之方式製 備,0.75克,.30毫莫耳),形成一種白色懸浮液,繼續攪拌, 使溫度回升至室溫(約30分鐘),然後加入溶解於乾燥的 DMF(1毫升)中之2,6-二氟11比唆(0.359毫升,3.96毫莫耳), 在5〇°C下攪拌1·5小時,冷卻至室溫,加入數滴水,減壓 下除去溶劑,殘留物經由Biotage SP1 (25+Μ矽膠管柱)純 化’以9:1至7:3的環己烧/EtOAc溶離,合併含產物之劃 分,減壓下濃縮,製得9〇毫克之純產物及18Q毫克的混 合物,其再經Biotage SP1 (25+M矽膠管柱)純化,以9:1 至7:3之環己烷/EtOAc溶離,合併含產物之劃分,減壓下 ,縮,再次溶解於DCM,合併第一次層析得之9〇毫克批 次,減壓濃縮,製得標題化合物(210亳克,19%)。 'H-NMR (500 MHz5 CDC13): δ 1.28 (t, 3Η) L7M.82 (m,2Η) ία].% (m, 2Η) 19〇_2 〇4 (功,2η) 2 〇6 2 ΐ8 ㈣ -107- 20 200838508 2H) 2·40_2·56 (m,1Η) 3·98 (s,2H) 4·15 (q,2H) 6·66 (dd, 1H) 7.78-7.84 (m,iH) 8.12 (d,1H); UPLC_MS: 0·79 分鐘, 323 [M+H]+ 〇 中間物64 烷-8-甲醛15 Under a nitrogen blanket, sodium hydride (〇·132 g, 3·30 mmol) was stirred in dry DMF (10 mL) and slowly added to dry DMF at 〇 ° C ( Ethyl (trans)-2-oxo-1-oxa-3-azaspiro[4·5]decane-8-carboxylate (10 ml) prepared in a manner similar to the preparation of intermediate 15 , 0.75 g, .30 mmol, formed a white suspension, stirring was continued, the temperature was allowed to rise to room temperature (about 30 minutes), and then 2,6-di dissolved in dry DMF (1 mL) was added. Fluorine 11 hydrazine (0.359 ml, 3.96 mmol), stir at 5 ° C for 1.5 hours, cool to room temperature, add a few drops of water, remove the solvent under reduced pressure, and pass the residue through Biotage SP1 (25+ Μ The ruthenium tube column was purified and dissolved in cyclohexanol/EtOAc at 9:1 to 7:3, and the product-containing fractions were combined and concentrated under reduced pressure to give a mixture of 9 mg of pure product and 18 Q of the mixture. Biotage SP1 (25+M 矽 rubber column) was purified, dissolved in 9:1 to 7:3 cyclohexane/EtOAc, combined with product partition, reduced under reduced pressure, redissolved in DCM, combined with first layer 9析G batch, concentrated under reduced pressure to give the title compound (210 milligrams, 19%). 'H-NMR (500 MHz5 CDC13): δ 1.28 (t, 3Η) L7M.82 (m, 2Η) ία].% (m, 2Η) 19〇_2 〇4 (gong, 2η) 2 〇6 2 ΐ8 (iv) -107- 20 200838508 2H) 2·40_2·56 (m,1Η) 3·98 (s,2H) 4·15 (q,2H) 6·66 (dd, 1H) 7.78-7.84 (m,iH) 8.12 (d,1H); UPLC_MS: 0·79 min, 323 [M+H]+ 〇 intermediate 64 alk-8-formaldehyde
將(反式)-3-(6-氟-2-吡啶基)-2-侧氧-1-氧雜-3-氮雜螺 [4·5]癸烧-8-羧酸乙酯(中間物幻,210毫克,0.652毫莫 耳),在氮氣層内,溶解於四氫呋喃(8毫升),將混合物冷 卻至-78°C ’慢慢地加入氫化鋁鋰(0.489毫升,0.489毫莫 耳,在THF内之1M溶液),再於_78t下攪拌2.5小時, 以乙謎(10亳升)稀釋,加入兩匙的硫酸鈉脫水劑,混合物 被激烈攪拌下,一邊讓溫度升至室溫(約3小時),沈澱經 由一種分離的管子過濾,經乙醚洗滌,在減壓下將混合物 濃縮,製得粗製品,藉由矽膠管柱層析法純化(Bi〇tage spi, 12+M管柱),以100:0至7〇:3〇之環己烷/Et〇Ac溶離,製 得此標題化合物,為一種白色固體(22毫克,12%)。 'H-NMR (400 MHz, CDCls): δ L75-2.05 (m5 6Η)(trans)-3-(6-fluoro-2-pyridyl)-2-oxo-1-oxa-3-azaspiro[4·5]indole-8-carboxylic acid ethyl ester (middle) Imaginary, 210 mg, 0.652 mmol, dissolved in tetrahydrofuran (8 mL) in a nitrogen blanket, and the mixture was cooled to -78 ° C. slowly, lithium aluminum hydride (0.489 mL, 0.489 m. The 1 M solution in THF was stirred for another 2.5 hours at _78 t, diluted with a riddle (10 liters), and two tablespoons of sodium sulfate dehydrating agent was added. The mixture was stirred vigorously while allowing the temperature to rise to room temperature ( After about 3 hours), the precipitate was filtered through a separate tube, washed with diethyl ether, and the mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (Bi〇tage spi, 12+M column) The title compound was obtained as a white solid (22 mg, 12%). 'H-NMR (400 MHz, CDCls): δ L75-2.05 (m5 6Η)
-108 200838508 2.08-2.21 (m? 2H) 2.43-2.53 (m5 1H) 3.94 (s? 2H) 6.63-6.70 (m,1H) 7.67-7.92 (m,1H) 8·11 (m,1H) 9·74 (s5 1H); UPLC-MS: 0.68 分鐘,279 [M+H]+。 也回收得(反式)-3-(6-氟-2-吼啶基)-8-(羥基甲基卜:^氧 雜-3-氮雜螺[4.5]癸烷-2-酮(74毫克,40%)之醇,為一種白 色固體;UPLC-MS: 0.61 分鐘,281 [M+Hf。 • 中間物65 (反式V8-(1H-1,2,3·苯莽三唆-1_基{『4-(2-吼哈甚 10 -2-基1胺基}曱基比咬基)-1-氧雜-3-氮雜螺『4 -2-酮-108 200838508 2.08-2.21 (m? 2H) 2.43-2.53 (m5 1H) 3.94 (s? 2H) 6.63-6.70 (m,1H) 7.67-7.92 (m,1H) 8·11 (m,1H) 9· 74 (s5 1H); UPLC-MS: 0.68 min, 279 [M+H]+. (trans)-3-(6-fluoro-2-acridinyl)-8-(hydroxymethylbu:^oxa-3-azaspiro[4.5]decane-2-one (74) was also recovered. Mg, 40%) of alcohol, a white solid; UPLC-MS: 0.61 min, 281 [M+Hf. • Intermediate 65 (trans V8-(1H-1,2,3·benzoquinone-1) _基{『4-(2-吼哈甚10 -2-yl 1amino} 曱 比 咬 ))-1-oxa-3-azaspiro"4 -2- ketone
15 將4-(2-ϋ比唆基)_1,3·嗟峻-2-胺(12·26毫克,0 069毫莫 耳)及IH-l,2,3-苯并三唑(8·24毫克,0·〇69毫莫耳)溶解於 乾燥甲苯(2毫升)中後,在氮氣層下,滴入溶解於甲苯(2 毫升)中之(反式>2-侧氧-M2-吼咬基Μ_氧雜_3_'氮雜螺 [4.5]癸烷-8-曱醛(可以類似於製備中間物26之二二 2〇毫克,0.077毫莫耳)溶液,將混合物攪拌過a工、衣1 ’ <仪5加執至 l〇〇°C,並在氮氣層下加熱3小時,冷卻至 … 至〉皿,加入環 己烷(5毫升),混合物被攪拌分鐘後,予r;、m上 丁从過濾,以環 -109 - 20 200838508 己烷洗滌,固態濾餅經真空乾燥,經乙酸乙酯洗滌’將洗 液合併,真空下濃縮,製得此標題化合物(36亳克)。 h-NMR (400 MHz,CDC13): δ 8·58 (1H,d),8·35 (1H, • d),8.26 (1Η,d),8·08 (1Η,d),7.82-7.99 (2Η,m),7·70-7·78 • 5 (2Η,m),7·54 (1Η,t),7·45-7·52 (1Η,m),7·36-7·43 (1Η,m), 7.16-7.24 (1H,m),7·06 (1H,dd),6·55 (1H,d),4·10 (1H,d), 4.06 (1H,d),2·62-2·75 (1H,m),2.46 (1H,brd),1·55-2·20 (6Ή,m),1.21-1 ·40 (2H,m)。 10 中間物66 比啶某vi.3-嚓唑-2-腙15 4-(2-indole fluorenyl)_1,3·嗟君-2-amine (12·26 mg, 0 069 mmol) and IH-l,2,3-benzotriazole (8· After dissolving in dry toluene (2 ml), it was dissolved in toluene (2 ml) under a nitrogen blanket (trans->2-side oxygen-M2-吼 Μ Μ _ oxa _3_' azaspiro[4.5] decane-8-furaldehyde (may be similar to the preparation of intermediate 26 228 mg, 0.077 mmol) solution, stir the mixture over a Work, clothing 1 ' < instrument 5 plus to l ° ° C, and heated under nitrogen for 3 hours, cooled to ... to the dish, add cyclohexane (5 ml), the mixture was stirred for a while, The title compound (36 制) was obtained by filtration from hexanes eluting with hexane-109 - 20 200838508 hexanes, and the solid cake was dried in vacuo and washed with ethyl acetate. g) NMR (400 MHz, CDC13): δ 8·58 (1H, d), 8.35 (1H, • d), 8.26 (1Η, d), 8·08 (1Η, d), 7.82 -7.99 (2Η,m),7·70-7·78 • 5 (2Η,m),7·54 (1Η,t),7·45-7·52 (1Η,m),7·36-7 ·43 (1Η, m), 7.16-7.24 (1H,m),7·06 (1H,dd),6·55 (1H,d),4·10 (1H,d), 4.06 (1H,d),2·62- 2·75 (1H,m), 2.46 (1H,brd),1·55-2·20 (6Ή,m),1.21-1 ·40 (2H,m). 10 Intermediate 66 than a certain vi.3 -carbazole-2-indole
在〇C下’將4-(2-π比σ定基)-l,3-嗟嗤-2_胺(1克,5·64 晕旲耳)>谷解於DMF(20宅升)後’加入Selectfluor (2.231 克,6.30毫莫耳),在室溫下將混合物攪拌2小時,然後以 DCM淋洗,收集有機層,將DCM蒸發,所得粗製品藉由 KP-NH筒Biotage 40M純化,以環己烷/EtOAc的混合液 >谷離’製得此標題化合物(34.5毫克)。 h-NMR (400 MHz,CDC13): δ 8·69·8·75 (1H,d), 7.71-7.84 (2Η5 m)? 7.18-7.25 (1Η? m)? 4.63-4.90 (2Η? brs); -110- C S ) 200838508 UPLC-MS: 0·37 分鐘,196 [M+Hf。 將較不純的化學品回收,再利用一種矽膠管柱40 Μ Biotage純化,以DCM/MeOH的梯度溶離,製得另一批標 ‘ 題產物(100毫克)。 -5 中間物67 4-溴-1-(四氫-2-某口坐Under 〇C, '4-(2-π ratio σ-based)-l,3-嗟嗤-2-amine (1 g, 5.64 syncope)> solution after DMF (20 liters) 'Addition of Selectfluor (2.231 g, 6.30 mmol), the mixture was stirred at room temperature for 2 hours, then rinsed with DCM, organic layer was collected, evaporated, and then evaporated, and the crude product was purified by KP-NH cartridge Biotage 40M. The title compound (34.5 mg) was obtained from EtOAc (EtOAc) h-NMR (400 MHz, CDC13): δ 8·69·8·75 (1H,d), 7.71-7.84 (2Η5 m)? 7.18-7.25 (1Η?m)? 4.63-4.90 (2Η? brs); -110- CS ) 200838508 UPLC-MS: 0·37 minutes, 196 [M+Hf. The less pure chemicals were recovered and purified by a guanidine column 40 Μ Biotage and eluted with a gradient of DCM/MeOH to give another batch of title product (100 mg). -5 Intermediate 67 4-Bromo-1-(tetrahydro-2-one sitting
將TFA(2.62微升,0.034毫莫耳)加至置於玻璃瓶中之 ίο 4_溴_1H_吡唑(1〇〇毫克,0.680毫莫耳)與3,4-二氫-2H-吡喃 (86毫克,1.021毫莫耳)之混合物内,將所得混合物搖動並 被加熱至80°C,經16小時,反應混合物被冷至室溫後, 0 置於二氯曱烷(5毫升)與稀的氫氧化鈉水溶液(1厘,2亳升) 間分配’經由一種疏水的燒結物(pjjase Seperator筒)過 15 濾,以更多的二氣曱烷洗滌,將合併的有機層在減壓下濃 縮,殘留物經由Biotage被純化(1〇%_3〇% EtOAc/環己燒; 25MSi〇2管柱),製得此標題化合物(148毫克),為一種無 色油質物。 WNMR (400 MHz,CDC13): δ 7·66 (1H,s),7·52 (1H, 20 s),5·33-5·42 (1Η,m),4·06 (1Η,dd),3·66_3·77 (1Η,m), 1·97-2·15 (3H,m),1.61-1.79 (3H,m); HPLC-MS: 2.00 分鐘, -111- 200838508 147 and 149 [M-C5H80+H].。 中間物68 3 - >臭細 1 -(四氣一2H- ^比p南一 2· )-1 Η- 口比 口坐Add TFA (2.62 μl, 0.034 mmol) to ίο 4_bromo_1H-pyrazole (1 mg, 0.680 mmol) and 3,4-dihydro-2H- in a glass vial. In a mixture of pyran (86 mg, 1.021 mmol), the mixture was shaken and heated to 80 ° C. After 16 hours, the reaction mixture was cooled to room temperature and then taken to dichloromethane (5 ml) ) Distribute between dilute aqueous sodium hydroxide solution (1 PCT, 2 liters) through a hydrophobic sinter (pjjase Seperator) through 15 filters, wash with more dioxane, and combine the organic layers. The title compound (148 mg) was obtained as a colorless oily material. WNMR (400 MHz, CDC13): δ 7·66 (1H, s), 7·52 (1H, 20 s), 5·33-5·42 (1Η, m), 4·06 (1Η, dd), 3·66_3·77 (1Η,m), 1·97-2·15 (3H,m),1.61-1.79 (3H,m); HPLC-MS: 2.00 minutes, -111- 200838508 147 and 149 [M- C5H80+H]. Intermediate 68 3 - > stinky 1 - (four gas - 2H - ^ ratio p south one 2 · ) - 1 Η - mouth ratio
此標題化合物係以類似於製備中間物67之方式製 備,使用3-溴-1Η-吡唑(100毫克,0.680毫莫耳),製得此 ίο 標題化合物(121毫克)。 h-NMR (400 MHz,CDC13): δ 7·53 (1Η,d),6·34 (1Η, d),5·35 (1Η,dd), 4·07 (1Η,dd),3·63賺3·79 (1Η,m)5 1.97-2.23 (3H,m),1·60-1·81 (3H,m); HPLC-MS: 1,93 分鐘, 馨 147 及 149 [M-C5H80+H]+ 15 中間物69 (反式氟笨基V1H-吡唑-3-基1胺基}甲 D-3_『1 -(izg i -2H-口% -2·Ρ_ 1H一口i _3-H一 1 一 1 # -3_ Ma 雜螺「4.51癸烷-2-酮 -112- 200838508The title compound was prepared in a similar manner to the preparation of Intermediate 67, using 3-bromo-1?-pyrazole (100 mg, 0.6. h-NMR (400 MHz, CDC13): δ 7·53 (1Η, d), 6·34 (1Η, d), 5·35 (1Η, dd), 4·07 (1Η, dd), 3.63 Earn 3.79 (1Η,m)5 1.97-2.23 (3H,m),1·60-1·81 (3H,m); HPLC-MS: 1,93 min, 147 and 149 [M-C5H80+ H]+ 15 Intermediate 69 (trans fluorophenyl V1H-pyrazol-3-yl 1 amine group} A D-3_『1 -(izg i -2H-port% -2·Ρ_ 1H a mouth i _3-H One 1 to 1 # -3_ Ma snail "4.51 decane-2-one-112- 200838508
1010
1515
將3·溴-1-(四氫-2H-吡喃-2-基)-1H-吡唑(中間物68, 53.7毫克,0.232毫莫耳)、(反式)-8-({[1-(2-氟苯基)-1Η』比 唑-3-基]胺基}曱基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮(以類 似於製備中間物19之方式製備,40毫克,0.116毫莫耳)、 碘化銅(1)(22.12毫克,0·116毫莫耳)、(+/+(反式)-1,2-二 胺基環己烷(26.5毫克,0.232毫莫耳)及三鹽基型磷酸鉀 (123毫克,0.581毫莫耳)之混合物溶解於二噚烷(3毫升) 後,被密封於一種玻璃管並在120Χ:下搖動20小時,冷卻 至室溫,蒸發除去溶劑,加入二氯曱烷(5毫升),過濾, 以更多的二氯曱烷(2 X 1毫升)洗滌,合併有機層,以ρΗ3 之檸檬酸缓衝(5毫升)洗滌,再經由一種疏水的燒結物 (Phase Seperator筒)過濾,濃縮之,殘留物經由Biotage 純化(30%-100%£沁八〇/環己烷;121^1^[管柱),製得此標 題化合物(45毫克),為一種無色油質物。 ^-NMR (400 MHz? CDC13): δ 7.82-7.93 (2Η? m)5 7.55 (1Η,d),7·11-7·26 (3Η,m),6·77 (IH,d),5·83 (1Η,d),5.26 (1H,dd),4J1 (1H,dd),3·92 (2H,s),3·72 (1H,td),3.17 (2H, d),1·92-2·22 (7H,m),1·79-1·92 (2H,m),1·56-1·79 (4H,m), -113- 200838508 1.12-1.31 (2H, m): m/z 495 [M+H]+ ^ 411 [M-C5H80+H]+ 中間物70 i反式)_8-({『l-(2_氤茉基V1H-吡唑-3-基1胺基}甲 基)-3·『Μ四氫-2H-吡喃-2-基V1H-吡唑-4-基Μ-氣雜-3-氮 雜螺『4.51癸烷-2-酮3·Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (intermediate 68, 53.7 mg, 0.232 mmol), (trans)-8-({[1 -(2-fluorophenyl)-1Η"pyrazol-3-yl]amino}indenyl)-1-oxa-3-azaspiro[4.5]decane-2-one (similar to preparation intermediate Prepared by the method of 19, 40 mg, 0.116 mmol, copper iodide (1) (22.12 mg, 0·116 mmol), (+/+(trans)-1,2-diamino ring A mixture of hexane (26.5 mg, 0.232 mmol) and tribasic potassium phosphate (123 mg, 0.581 mmol) was dissolved in dioxane (3 mL) and sealed in a glass tube at 120 Χ: After shaking for 20 hours, it was cooled to room temperature, the solvent was evaporated, then dichloromethane (5 ml) was added, filtered, washed with more dichloromethane (2 X 1 ml) Wash with acid buffer (5 ml), filter through a hydrophobic sinter (Phase Seperator cartridge), concentrate, and purify the residue via Biotage (30%-100% 沁 〇 环 / cyclohexane; 121 ^ 1 ^ The title compound (45 mg) was obtained as a colorless oil. ^-NMR (400 MHz? CDC13): δ 7.82-7.93 (2Η? m)5 7.55 (1Η,d),7·11-7·26 (3Η,m),6·77 (IH,d),5 ·83 (1Η,d), 5.26 (1H,dd),4J1 (1H,dd),3·92 (2H,s),3·72 (1H,td),3.17 (2H, d),1·92 -2·22 (7H,m),1·79-1·92 (2H,m),1·56-1·79 (4H,m), -113- 200838508 1.12-1.31 (2H, m): m /z 495 [M+H]+ ^ 411 [M-C5H80+H]+ Intermediate 70 i trans) _8-({『l-(2_氤茉基V1H-pyrazol-3-yl 1 amine group) }Methyl)-3·ΜΜtetrahydro-2H-pyran-2-yl V1H-pyrazole-4-ylindole-gas hetero-3-azaspiro”4.51 decane-2-one
1010
此標題化合物係以類似於製備中間物69之方式製 備,將3-溴-1-(四氳-2Η-吡喃-2-基)-1Η-吡唑換成4-溴 -1-(四氫-2Η_吡喃-2-基)-1Η-吡唑(中間物67,40.3毫克, 0.174毫莫耳),製得標題化合物(48毫克)。 ^-NMR (400 MHz,CDC13): δ 7·94 (1Η,s),7.82-7.90 (2Η,m),7.55 (1Η,s),7·11-7·26 (3Η,m),5·83 (1Η,d),5·36 (1H? dd)5 4.02-4.10 (1H? m)5 3,64-3.75 (1H5 m)5 3.68 (2H5 s)5 3·19(2Η,d),1·95-2·21 (7H,m),1·87 (2H,td),1.55画 1·81 (4H, m),L12-1.26 (2H,m): HPLC-MS:2.56 分鐘,411 [M - C5H80+H]+。 中間物71 -114- 15 200838508 8-氟-2-侧氣-3-(2-吡啶基VI-氣雜-3-氮雜螺『4.51癸烷-8-羧 酸乙酯This title compound was prepared in a similar manner to the preparation of intermediate 69, which was replaced with 3-bromo-1-(tetramethylene-2-pyran-2-yl)-1 oxime-pyrazole. Hydrogen-2Η-pyran-2-yl)-1Η-pyrazole (Intermediate 67, 40.3 mg, 0.174 mmol) gave the title compound (48 mg). ^-NMR (400 MHz, CDC13): δ 7·94 (1Η, s), 7.82-7.90 (2Η, m), 7.55 (1Η, s), 7·11-7·26 (3Η, m), 5 ·83 (1Η,d),5·36 (1H? dd)5 4.02-4.10 (1H? m)5 3,64-3.75 (1H5 m)5 3.68 (2H5 s)5 3·19(2Η,d) ,1·95-2·21 (7H,m),1·87 (2H,td), 1.55,1·81 (4H, m), L12-1.26 (2H,m): HPLC-MS: 2.56 min, 411 [M - C5H80+H]+. Intermediate 71-114- 15 200838508 8-Fluoro-2-side gas-3-(2-pyridyl VI-aza-3-azaspiro"4.51 decane-8-carboxylate
1010
15 將溶解於THF(45毫升)的(反式)-2-侧氧-3-(2-吡啶 基)-1-氧雜-3-氮雜螺[4.5]癸烷-8-羧酸乙酯(可以類似於製 備中間物54之方式製備,500毫克,1.643毫莫耳)與 LDA(1.8 M,2.74毫升,4·93毫莫耳)的溶液冷卻至-78°C, 並在此溫度下攪拌0.5小時後,加入N-氟苯磺亞醯胺(1036 毫克,3.29毫莫耳),在-78°C下將反應再攪拌3小時,將 反應混合物倒入水中,以乙醚萃取兩遍,合併的有機層以 硫酸鈉乾燥,蒸發除去溶劑,製得的粗製品以矽膠管柱純 化,以環己烷/乙酸乙酯溶離(自10至100),製得標題化合 物(249.5毫克,42%收量),為兩種比例為〜60··40的異構物 之混合物。 ^-NMR (400 MHz, CDC13): δ 1.30-1.37 (m5 3Η) 1.92-2.14 (m5 4H) 2.15-2.27 (m5 2H) 2.28-2.38 (m5 1H) 2.38-2.48 (m9 1H) 4.02 (s? 1H) 4.11 (s5 1H) 4.23-4.32 (m5 2H) 7·02-7·09 (m,1H) 7.69-7.76 (m,1H) 8·15-8·36 (m,2H)。 -115- 200838508 中間物72及73 8-氤-8-(羥基曱基)-3-(2-吡啶基VI-氣雜-3_氮雜螺「4.51癸 烷-2-酮(中間物72)及8-氟-8-(羥基甲基)-3-(2-吡啶基VI-氣雜-3-氮雜螺「4.51-癸烷-2-酮(中間物73)15 (trans)-2-oxo-3-(2-pyridyl)-1-oxa-3-azaspiro[4.5]decane-8-carboxylic acid B dissolved in THF (45 mL) The ester (prepared analogously to the preparation of intermediate 54 and 500 mg, 1.643 mmol) was cooled to -78 ° C with a solution of LDA (1.8 M, 2.74 mL, 4.93 mmol) at this temperature. After stirring for 0.5 hour, N-fluorobenzenesulfonamide (1036 mg, 3.29 mmol) was added, and the reaction was stirred at -78 ° C for further 3 hours. The reaction mixture was poured into water and extracted twice with diethyl ether. The combined organic layer was dried with sodium sulfate (MgSO4). % yield) is a mixture of two isomers of ratio ~60·.40. ^-NMR (400 MHz, CDC13): δ 1.30-1.37 (m5 3Η) 1.92-2.14 (m5 4H) 2.15-2.27 (m5 2H) 2.28-2.38 (m5 1H) 2.38-2.48 (m9 1H) 4.02 (s? 1H) 4.11 (s5 1H) 4.23-4.32 (m5 2H) 7·02-7·09 (m, 1H) 7.69-7.76 (m, 1H) 8·15-8·36 (m, 2H). -115- 200838508 Intermediate 72 and 73 8-氤-8-(hydroxyindenyl)-3-(2-pyridyl VI-gas-hetero-3_azaspiro"4.51 decane-2-one (intermediate 72 And 8-fluoro-8-(hydroxymethyl)-3-(2-pyridyl VI-aza-3-azaspiro"4.51-decan-2-one (intermediate 73)
此標題化合物係以類似於製備中間物23之方式製 備,使用8-氟-2-侧氧-3-(2-吡啶基)-1-氧雜-3_氮雜螺[4.5] 癸烷-8-羧酸乙酯(以類似於製備中間物71之方式製備, 315毫克,0.977毫莫耳)(製得(136.3毫克,47%)的主異構 ίο 物中間物72及(84.9毫克,30%)的次異構物中間物73。 中間物72 ^-NMR (500 MHz5 CDC13): δ 8.32 (1Η, d)? 8.24 (1H5 d),7·73 (1H,t),7·09-7·01 (1H,m)5 4·01 (2H,s)5 3·64 (2H, 15 dd),2·15-1·79 (8H,m),1·76 (1H,t); UPLC-MS: 0.65 分鐘, 281 [M+Hf 〇 中間物73 4 NMR (500 MHz,CDC13): δ 8·32 (1H,d),8.27 (1H, 20 d),7·73 (1H,t),7·10-7·02 (1H,m),4·06 (2H,s),3·64 (2H, dd),2.30-2.10 (4H,m),1·95-1·77 (2H,m),1.77-1.53 (3H, -116- 200838508 m); UPLC-MS: 0.63 分鐘,281 [M+H]+。 - 中間物74 .5 8-氟-2-侧氣-3-(2-吡啶基VI-氣雜-3-氮雜螺C4.51癸烷-8-甲 藍This title compound was prepared in a similar manner to the preparation of intermediate 23 using 8-fluoro-2-oxo-3-(2-pyridyl)-1-oxa-3-azaspiro[4.5] decane- Ethyl 8-carboxylate (prepared analogously to the preparation of intermediate 71, 315 mg, 0.977 mmol) (yield (136.3 mg, 47%) of the main isomers intermediate 72 and (84.9 mg, 30%) of the sub-isomer intermediate 73. Intermediate 72 ^-NMR (500 MHz 5 CDC13): δ 8.32 (1Η, d)? 8.24 (1H5 d), 7.73 (1H, t), 7.09 -7·01 (1H,m)5 4·01 (2H,s)5 3·64 (2H, 15 dd), 2·15-1·79 (8H,m),1·76 (1H,t) UPLC-MS: 0.65 min, 281 [M+Hf 〇 intermediate 73 4 NMR (500 MHz, CDC13): δ 8·32 (1H, d), 8.27 (1H, 20 d), 7·73 (1H, t),7·10-7·02 (1H,m),4·06 (2H,s),3·64 (2H, dd), 2.30-2.10 (4H,m),1·95-1·77 (2H, m), 1.77-1.53 (3H, -116-200838508 m); UPLC-MS: 0.63 min, 281 [M+H]+ - Intermediate 74.5 8-Fluoro-2-Side-3 -(2-pyridyl VI-aza-3-azaspiro-C4.51 decane-8-methyl blue
此標題化合物係以類似於製備中間物23之方式製 備,使用8-氟-8-(羥基曱基)-3-(2-吼啶基)-1-氧雜-3-氮雜螺 1〇 (4.5)癸烷-2-酮(中間物72, 135毫克,0.482毫莫耳),製得 此標題化合物(116毫克,69.2%)。 lR NMR (500 MHz5 CDC13): δ 9.75 (1Η, d)5 8.32 (1H? • d),8.24 (1H,d),7.79-7.66 (1H,m),7.10-7.01 (1H,m),4·03 (2H,s),2·40-1·69 (8H,m); UPLC-MS: 0·59 分鐘,279 is [M+H]+及 297 [M+H20+Hf 中間物75 8-氟-2-侧氣-3-(2-吡啶基M-氣雜_3-氮雜螺「4.51癸烷-8-甲 經 -117- 20 200838508This title compound was prepared in a similar manner to the preparation of intermediate 23 using 8-fluoro-8-(hydroxyindolyl)-3-(2-indridinyl)-1-oxa-3-azaspiroindole. (4.5) decane-2-one (Intermediate 72, 135 mg, 0.482 mmol). lR NMR (500 MHz5 CDC13): δ 9.75 (1Η, d)5 8.32 (1H? • d), 8.24 (1H, d), 7.79-7.66 (1H, m), 7.10-7.01 (1H, m), 4 ·03 (2H, s), 2·40-1·69 (8H, m); UPLC-MS: 0·59 minutes, 279 is [M+H]+ and 297 [M+H20+Hf Intermediate 75 8 -Fluoro-2-side gas-3-(2-pyridyl M-gashetero-3-azaspiro"4.51 decane-8-A-117- 20 200838508
此標題化合物係以類似於製備中間物23之方式製 備,使用8-氟-8-(羥基曱基)-3-(2-吼啶基)-1-氧雜-3-氮雜螺 [4.5]癸烷-2-酮(中間物73, 83毫克,0.296毫莫耳),製得此 標題化合物(50毫克,57.6%)。 !H NMR (500 MHz? CDC13): δ 9.82 (1Η5 d), 8.34 (1Η, d),8·26 (1Η,d),7·74 (1Η,ί),7·11-7·03 (1Η,m),4·09 (2Η,s), 2.32-1.76 (8H,m); UPLC-MS: 0·58 分鐘,279 [M+H]+及 297 [M+H20+H]+。 10 中間物76 1二(2 -亂本基哇-3 -胺This title compound was prepared in a similar manner to the preparation of intermediate 23 using 8-fluoro-8-(hydroxyindolyl)-3-(2-indridinyl)-1-oxa-3-azaspiro[4.5 The title compound (50 mg, 57.6%) was obtained from the title compound. !H NMR (500 MHz? CDC13): δ 9.82 (1Η5 d), 8.34 (1Η, d), 8·26 (1Η, d), 7·74 (1Η, ί), 7·11-7·03 ( 1Η, m), 4·09 (2Η, s), 2.32-1.76 (8H, m); UPLC-MS: 0·58 minutes, 279 [M+H]+ and 297 [M+H20+H]+. 10 Intermediate 76 1 2 (2 - chaotic Benja-3 - amine
將Η2-氟苯基)-1Η-η比唑_3_胺(〗克,5.64毫莫耳) (N2911-53-1)溶解於N,N_二甲基甲醯胺(2〇毫升)後 ,力α入 Ν-蛾號賴亞胺(1 333克,5 93毫莫耳),在室溫下將混合 物攪拌3小時,減壓下除去DMF,粗製化合物被溶解於 -118- 15 200838508 100毫升的AcOEt内,有機層經溶在水中之50毫升的1〇% Na^O3溶液及50毫升的鹽水洗滌後,以Na2s〇4乾燥, 過濾,濃縮至乾,殘留物再經快速層析法純化(bIOTAGE, redistep 40克矽膠管柱),以下述梯度進行:A:環己烷/B:Dissolving Η2-fluorophenyl)-1Η-η-razole-3-amine (〗 〖g, 5.64 mmol) (N2911-53-1) in N,N-dimethylformamide (2 mL) After that, the force was introduced into Ν-moth imide (1 333 g, 5 93 mmol), the mixture was stirred at room temperature for 3 hours, DMF was removed under reduced pressure, and the crude compound was dissolved in -118- 15 200838508 In 100 ml of AcOEt, the organic layer was washed with 50 ml of 1% Na 2 O 3 solution and 50 ml of brine dissolved in water, dried over Na 2s 〇 4, filtered and concentrated to dryness. Purification (bIOTAGE, redistep 40 g 矽 rubber column), with the following gradient: A: cyclohexane / B:
AcOEt: 0% B,3 分鐘,〇%至 15% B,20 分鐘,15% B,5 分 鐘,製得此標題化合物,為一種棕色固體(1.4156克,81%). Rf = 0.17 (環己烷 9/AcOEt 1); h-NMR (400 MHz,CDC13): δ 7·88 (d,1H),7·78-7·85 (m,1H),7·12-7·26 (m,3H),3.98 (s, 2H): HPLC-MS: 1·72 分鐘,303.9 [M+H]+; 土間物77 L^A_)-8-({『l-(2二氟笨某碘-if吡唑-3-某·!胺基}甲 基比咬基)士氧雜-3-i.雜螺「4.51癸烷讎2-酮AcOEt: 0% B, 3 min, 〇% to 15% B, 20 min, 15% B, 5 min, to give the title compound as a brown solid (1.4156 g, 81%). Rf = 0.17 Alkane 9/AcOEt 1); h-NMR (400 MHz, CDC13): δ 7·88 (d, 1H), 7·78-7·85 (m, 1H), 7·12-7·26 (m, 3H), 3.98 (s, 2H): HPLC-MS: 1·72 min, 303.9 [M+H]+; soil 77 L^A_)-8-({『l-(2 difluoro stupid iodine- If pyrazole-3-some·!amino}methyl than bite) oxathia-3-i. heterosole "4.51 decane oxime 2-ketone
將(反式)-2-侧氧_3_&吡啶基氧雜_3_氮雜螺[4 5] 8-曱盤(可根據中間物26的製法製備,337毫克,1.295 ^莫耳)及1-(2-氟苯基)冰碘-in-吡唑_3_胺(中間物76, 392 毛克,1.295毫莫耳)溶解於丨,2_二氯乙烷(4毫升)後,加入 •119- 200838508 異丙氧化鈦(IV)(0.759毫升,2 59毫莫耳),在6〇。〇下將混 合物加熱6小時35分鐘,冷卻至室溫,加入甲醇(2·56毫 升),再加入氫硼化鈉(147毫克,3.88毫莫耳),在室溫下 攪拌14小時50分鐘,加入1〇毫升飽和的碳酸鉀溶液, 5 混合物在室溫下被攪拌5分鐘,過濾,濾餅以75毫升的a (trans)-2-sideoxy_3_&pyridyloxa-3-azaspiro[4 5] 8-pinium disk (prepared according to the preparation method of intermediate 26, 337 mg, 1.295 mmol) and 1-(2-fluorophenyl) ice iodine-in-pyrazole_3_amine (intermediate 76, 392 gram, 1.295 mmol) dissolved in hydrazine, 2-dichloroethane (4 ml), Add • 119- 200838508 Titanium Oxide (IV) (0.759 ml, 2 59 mmol) at 6 〇. The mixture was heated for 6 hours and 35 minutes under cooling, cooled to room temperature, then methanol (2·56 ml) was added, then sodium borohydride (147 mg, 3.88 mmol) was added and stirred at room temperature for 14 hours and 50 minutes. Add 1 ml of saturated potassium carbonate solution, 5 and mix at room temperature for 5 minutes, filter, filter cake to 75 ml
AcOEt洗滌,將此雙層溶液轉置至一種分液漏斗,保留有 機層’水溶液層再以25毫升之AcOEt萃取,合併有機層 以25毫升的鹽水再洗一遍,以Na2s〇4乾燥,過濾,濃縮 至乾,殘留物再經快速層析法純化(ISC〇 companion, 10 120克矽膠管柱),以下述梯度溶離:A:環己烷/B: AcOEt: 0% B,3.5 分鐘,〇〇/〇至 10% b,10·5 分鐘内,1〇% b,9 3 分 鐘,10%至25% Β,8.2分鐘,25% Β,10.5分鐘,製得標題 化合物,為一種棕色油質物(482毫克,65%),Rf= 0.04 (環 己烷 9/AcOEtl); 15 'H-NMR (400 MHz, CDC13): δ 8.33-8.36 (m? 1H)5 8.26-8.31 (m,1H),7·84-7·92 (m5 2H),7·66-7·77 (m, 1H), ® 7·13-7·27 (m,3H),7·02-7·08 (m,1H),4.07 (s,2H),3·78 (t, 1H),3·29 (V2H),1.98_2.10 (m,3H),1·62-1·96 (m,4H), 1.13-1.35 (m,2H); HPLC-MS: 2.97 分鐘,548·1 [M+Hf。 中間物78 4-氤-1-(2-氟笨基Vl/ί-吡崦-3_胺 -120- 200838508The AcOEt was washed, the two-layer solution was transferred to a separatory funnel, and the organic layer was retained. The aqueous layer was extracted with 25 ml of AcOEt. The combined organic layers were washed again with 25 ml of brine, dried over Na 2 s 4 and filtered. Concentrated to dryness and the residue was purified by flash chromatography (EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc /〇 to 10% b, 10·5 minutes, 1〇% b, 9 3 minutes, 10% to 25% Β, 8.2 minutes, 25% Β, 10.5 minutes, the title compound is obtained as a brown oily substance ( 482 mg, 65%), Rf = 0.04 (cyclohexane 9/AcOEtl); 15 'H-NMR (400 MHz, CDC13): δ 8.33-8.36 (m? 1H)5 8.26-8.31 (m,1H), 7·84-7·92 (m5 2H), 7·66-7·77 (m, 1H), ® 7·13-7·27 (m, 3H), 7·02-7·08 (m, 1H) ), 4.07 (s, 2H), 3·78 (t, 1H), 3·29 (V2H), 1.98_2.10 (m, 3H), 1.62-1·96 (m, 4H), 1.13- 1.35 (m, 2H); HPLC-MS: 2.97 min, 548·1 [M+Hf. Intermediate 78 4-氤-1-(2-Fluoro-based Vl/ί-pyridin-3-amine -120- 200838508
將1-(2-氟苯基)_m-吡唑_3_胺(可根據J.Org.Cliem. 2005, 70, 922中描述的方法製備,3〇〇毫克,1.693毫莫耳) 溶解於四氫呋喃(6毫升),再加入N-氟(苯基磺醯基)苯 • 磺醯胺(561毫克,1·778毫莫耳),在60°C下將混合物攪拌 23小時,溫度降至室溫後,加入5毫升的MeOH,將此溶 液通過一種20克SCX筒,以50毫升的MeOH洗滌二遍, 以75毫升,在甲醇内之2MNH3溶液將化合物釋放出來, 減壓下除去溶劑,粗製品藉由快速層析法被純化(ISCO 10 COMPANION,12 克矽膠管柱)·· A:環己烷/B: AcOEt: 0% Β,1·8 分鐘,0%至 25% B,17.9 分鐘,25% B,3.6 分鐘, 製得此標題化合物,為一種棕色固體(22.3毫克,6%)。 _ W-NMR (400 MHz,CDC13): δ 7·73·7·85 (m,2Η), 7·08·7·25 (m,3Η),3·85 (brs,2H); HPLC-MS: 1·94 分鐘, 15 196.1 [Μ+Η]+; 中間物79 (反式氟·1-(2·氟笨基吡唑-3-基1胺基}曱 基)-1-氣雜-3-氮雜螺「4.51癸^^1-(2-Fluorophenyl)-m-pyrazole-3-amine (prepared according to the method described in J. Org. Cliem. 2005, 70, 922, 3 mg, 1.693 mmol) Tetrahydrofuran (6 ml), followed by N-fluoro(phenylsulfonyl)benzenesulfonamide (561 mg, 1.778 mmol), the mixture was stirred at 60 ° C for 23 hours and the temperature was lowered to room. After warming, 5 ml of MeOH was added, the solution was passed through a 20 g SCX cartridge, washed twice with 50 ml of MeOH, and 75 ml of a solution of 2M NH3 in methanol was evaporated. The product was purified by flash chromatography (ISCO 10 COMPANION, 12 g 矽 rubber column) · A: cyclohexane / B: AcOEt: 0% Β, 1 · 8 min, 0% to 25% B, 17.9 min The title compound was obtained as a brown solid (22.3 mg, 6%). _ W-NMR (400 MHz, CDC13): δ 7·73·7·85 (m, 2Η), 7·08·7·25 (m, 3Η), 3·85 (brs, 2H); HPLC-MS : 1·94 minutes, 15 196.1 [Μ+Η]+; Intermediate 79 (trans-fluoro·1-(2·fluoro]pyrazol-3-yl 1amino}indenyl)-1-gas- 3-aza snail "4.51 癸 ^^
-121- 200838508-121- 200838508
5 105 10
此標題化合物係以類似於製備中間物77之方式製 備,使用(反式)-2-侧氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛 (可以類似於製備中間物18之方式製備,141毫克,0.769 毫莫耳)及4-氟氟苯基)-1Η-吡唑-3-胺(以類似於製備 中間物78之方式製備,150毫克,0.769毫莫耳),製得此標 題化合物,為一種白色固體(144毫克,51%)。 ^-NMR (400 MHz? CDC13): δ 7.76-7.87 (m5 2Π)? 7.09-7.24 (m,3Η),5.13 (s,1Η),3.69 (t,1Η),3.37-3.44 (m, 2H),3.26 (t, 2H),1.93-2.06 (m,4H),1·71-1·89 (m,3H), 1.06-1.22 (m,2H); R产0·53 (AcOEt); UPLC-MS: 0·69 分鐘, 363.03 [M+H]+,725.09 [2M+H]+; 中間物80 15 (反式V2-侧氣-3-(3-噠畊基)-1-氣雜-3-氮雜螺『4.51癸烷-8- 羧酸乙酯This title compound was prepared in a similar manner to the preparation of intermediate 77 using (trans)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-furfural (may be similar Prepared by the preparation of intermediate 18, 141 mg, 0.769 mmol, and 4-fluorofluorophenyl)-1 -pyrazol-3-amine (prepared analogously to the preparation of intermediate 78, 150 mg, 0.769 m The title compound was obtained as a white solid (144 mg, 51%). ^-NMR (400 MHz? CDC13): δ 7.76-7.87 (m5 2Π)? 7.09-7.24 (m,3Η), 5.13 (s,1Η), 3.69 (t,1Η), 3.37-3.44 (m, 2H) , 3.26 (t, 2H), 1.93-2.06 (m, 4H), 1·71-1·89 (m, 3H), 1.06-1.22 (m, 2H); R production 0·53 (AcOEt); UPLC- MS: 0·69 minutes, 363.03 [M+H]+, 725.09 [2M+H]+; Intermediate 80 15 (trans V2-side gas-3-(3-哒耕基)-1-gas- 3-Azaspiro"4.51 decane-8-carboxylic acid ethyl ester
-122- 200838508 將(順式)-2-侧氧小氧雜·3_氮雜螺[4·5]癸烷_8_羧酸乙 酯(以類似於製備中間物16之方式製備,10克,44.0毫莫 = )]Κ3Ρ〇4(28.0克,132毫莫耳)、碘化銅⑴(〇·838克,4屬 笔莫^1)及3-氯噠畊(6〇5克,52·8毫莫耳)一起置於一種 〇I升脫除空氣的反應瓶内,並在氮氣層中,再懸浮 於1,4=’烧(150毫升)内,加入反式n胺基環己燒 (1·〇58耄升,8.80亳莫耳)至此所得之棕色混合物,然後將 鲁 反應加熱迴流(外部溫度13(rc,内部溫度1〇5。^,在此溫 度下攪拌約24小時然後中止反應反應混合物置入於 10 DCM(1000毫升),倒入含有1〇毫升氫氧化銨之水(3〇〇毫 升)中,攪拌10分鐘後,有機層以水(2X100毫升)及鹽水 (2X100耄升)洗滌’經nmO4乾燥,過濾,濃縮,粗製品 再經Biotage SP1純化兩次,以一種65i瓦膠管柱,使用 環己烷/EtOAc作為溶離液,製得標題化合物(1·6克); 15 !H.NMR (400 MHz5 CDC13): δ 8.96 (dd? 1Η)? 8.56 (dd5 1Η)? 7·50 (dd5 1Η),4·20 (s5 2Η),4·18 (q,2Η),2.51 (sept,1Η), 2·〇7-2·18 (m,2Η),1.97-2.06 (m,2Η),1·87-1·96 (m,2Η), 1·75-1·86 (m,2Η),1·29 (t,3H); UPLOMS: 0·60 分鐘,306 [Μ+Η]+ 〇 20 也分離得到差向異構物,(順式侧氧-3-(3-噠π井 基>1-氧雜-3-氮雜螺[4·5]癸烷I羧酸乙酯(5·〇克); ^-NMR (400 MHz5 CDCI3): δ 8.96 (dd, 1Η)? 8.57 (dd5 1Η)? 7·50 (dd,1Η),4.18 (q,2Η),4.14 (s,2Η),2·41 (sept,m), 2·12-2·21 (m,2H),1·95-2·10 (m,4H),1·65-1·76 (m,2H), -123- ί 1 ) 200838508 1.29 (t5 3H)。 中間物81 • ί反式)-8-(羥基曱基)-3-(3-噠畊基VI-氣雜-3-氮雜螺『4.51癸 ,5 烧-2-酮-122- 200838508 Ethyl (cis)-2-oxooxythiazepine-3-azoxaspiro[4.5]decane-8-carboxylate (prepared analogously to the preparation of intermediate 16 , 10 Grams, 44.0 millimoles = )] Κ 3 Ρ〇 4 (28.0 grams, 132 millimoles), copper iodide (1) (〇 · 838 grams, 4 pens ^ 1) and 3-chlorine ploughing (6 〇 5 grams, 52·8 millimolar) together in a 〇I liter air removal reaction bottle, and in a nitrogen layer, resuspended in 1,4 = 'burn (150 ml), add trans n-amine ring The brown mixture obtained by the calcination (1·〇58 liters, 8.80 Torr), and then the Ru reaction was heated to reflux (external temperature 13 (rc, internal temperature 1 〇 5. ^, stirring at this temperature for about 24 hours) Then, the reaction mixture was suspended in 10 DCM (1000 ml), poured into water (3 ml) containing 1 ml of ammonium hydroxide, and after stirring for 10 minutes, the organic layer was water (2×100 ml) and brine ( 2X100 liters) Washed <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 15!H.NMR (400 MHz5 CDC13): δ 8.96 (dd? 1Η)? 8.56 (dd5 1Η)? 7·50 (dd5 1Η), 4·20 (s5 2Η), 4·18 (q, 2Η) ), 2.51 (sept, 1Η), 2·〇7-2·18 (m, 2Η), 1.97-2.06 (m, 2Η), 1·87-1·96 (m, 2Η), 1·75-1 · 86 (m, 2 Η), 1 · 29 (t, 3H); UPLOMS: 0 · 60 minutes, 306 [Μ + Η] + 〇 20 also isolated to obtain the epimer, (cis side oxygen-3- (3-哒π well base > 1-oxa-3-azaspiro[4·5]decane Icarboxylic acid ethyl ester (5·〇克); ^-NMR (400 MHz5 CDCI3): δ 8.96 ( Dd, 1Η)? 8.57 (dd5 1Η)? 7·50 (dd, 1Η), 4.18 (q, 2Η), 4.14 (s, 2Η), 2·41 (sept, m), 2·12-2·21 (m, 2H), 1·95-2·10 (m, 4H), 1·65-1·76 (m, 2H), -123- ί 1 ) 200838508 1.29 (t5 3H). Intermediate 81 • ί Trans)-8-(hydroxyindenyl)-3-(3-indole-based VI-gas-aza-aza-spiro"4.51癸,5-burn-2-one
此標題化合物係以類似於製備中間物22之方式製 備,使用(反式)-2-侧氧-3-(3-噠畊基)-1-氧雜-3-氮雜螺[4.5] 1〇 癸烷-8-羧酸乙酯(中間物80, 1·6克,5.24毫莫耳),製得此 標題化合物(1.1克)。 h-NMR (400 MHz,CDC13): δ 8.97 (dd,1Η),8·56 (dd, • 1Η),7·50 (dd,1Η),4·21 (s,2Η),3·55 (d,2Η),1·83-2·08 (m, 6H)5 1.57-1.72 (m? 1H)? 1.15-1.29 (m? 2H); UPLC-MS: 0.44 15 分鐘,264 [M+Hf。 中間物82 (反式)-2-側氣-3-(3-噠畊基)-1-氣雜-3-氪雜螺f4.51癸烷-8- 曱醛 -124- 20 200838508This title compound was prepared in a similar manner to the preparation of intermediate 22 using (trans)-2-oxo-3-(3-indole)-1-oxa-3-azaspiro[4.5] Ethyl decane-8-carboxylate (Intermediate 80, 1.6 g, 5.24 mmol). h-NMR (400 MHz, CDC13): δ 8.97 (dd, 1Η), 8·56 (dd, • 1Η), 7·50 (dd, 1Η), 4·21 (s, 2Η), 3·55 ( d, 2Η), 1·83-2·08 (m, 6H)5 1.57-1.72 (m? 1H)? 1.15-1.29 (m? 2H); UPLC-MS: 0.44 15 minutes, 264 [M+Hf. Intermediate 82 (trans)-2-side gas-3-(3-哒耕基)-1-gasa-3-indene snail f4.51 decane-8-furfural -124- 20 200838508
此標題化合物係以類似於製備中間物23之方式制 備’使用(反式)-8(經基曱基)_3-(3-噠。井基)小氧雜_3•氣雜 螺[4.5]癸烧-2-酮’中間物81,500毫克,ΐ·9〇亳莫耳),制 得此標題化合物(490毫克)。 ^ iH-NMR (400 MHz,CDC13): δ 9·73 (s,1Η),8.95 (dd 1Η),8·54 (dd,1Η),7.49 (dd,1Η),4·13 (s,2Η),2·44-2·53 (m 1H),2·10-2.20 (m,2H),1·77·2·02 (m,6H); UPLC-MS: 〇 : 分鐘,262 [M+H]+。 · 中間物83 (W_4_胺基_4_(乙氧基)-l,l,l_三氟_3_ 丁埽·2_酮This title compound was prepared in a manner similar to the preparation of intermediate 23 'Using (trans)-8 (via fluorenyl)_3-(3-哒. well base) small oxa-3 oxaspiro[4.5] The title compound (490 mg) was obtained from EtOAc (yield: 81,500 mg, EtOAc). ^ iH-NMR (400 MHz, CDC13): δ 9·73 (s, 1Η), 8.95 (dd 1Η), 8.54 (dd, 1Η), 7.49 (dd, 1Η), 4·13 (s, 2Η) ), 2·44-2·53 (m 1H), 2·10-2.20 (m, 2H), 1·77·2·02 (m, 6H); UPLC-MS: 〇: minute, 262 [M+ H]+. · Intermediate 83 (W_4_Amino_4_(ethoxy)-l,l,l_trifluoro_3_丁埽·2_one
對溶解於曱醇之2·0Μ之氨水溶液(1178亳升, 耄莫耳)’在室溫下,加入溶解於乾燥乙腈(9·5毫升)中之 4,4-雙(乙基氧)-ΐ,ι,ΐ-三氟丁烯_2_酮溶液(根據在 Synthesis 1986, 1013-1014中描述之方式製備,5〇〇毫克, 2.357毫莫耳),在氮氣層下將混合物攪拌2小時,真空下 -125- 200838508 除去溶劑,殘留物溶解於DCM,經水洗滌後,再以Dcm 萃取,合併的有機萃取層被乾燥(NajCU),過濾及在真空 下濃縮,製得此標題化合物(406毫克,94%),未再梦= 下被使用。 5 1h-NMR (400 MHz,CDC13): δ 9·52-10·05 (m,1H) 5·45-5·87 (m,1Η),5·14 (s,1Η),4·16 (q,2Η),1·42 (t,3Η): UPLC-MS: 0.59 分鐘,184 [M+H]+。 ’ 中間物84 10 1_(2-氟笨基)_5-(三氟甲基νΐ7ίί-ρ比峻-3-胺Add 4,4-bis(ethyloxy) dissolved in dry acetonitrile (9.5 ml) to a solution of 2% aqueous ammonia (1178 liters, oxime) dissolved in decyl alcohol at room temperature. - ΐ, ι, ΐ-trifluorobutene-2-one solution (prepared according to the method described in Synthesis 1986, 1013-1014, 5 〇〇 mg, 2.357 mmol), stirring the mixture under a nitrogen blanket 2 The solvent was removed in vacuo, the residue was dissolved in DCM, washed with water and then purified eluting with EtOAc. (406 mg, 94%), not used again = under use. 5 1h-NMR (400 MHz, CDC13): δ 9·52-10·05 (m, 1H) 5·45-5·87 (m, 1Η), 5·14 (s, 1Η), 4·16 ( q, 2Η), 1·42 (t, 3Η): UPLC-MS: 0.59 minutes, 184 [M+H]+. ' Intermediate 84 10 1_(2-fluorophenyl)_5-(trifluoromethyl νΐ7ίί-ρ ratio jun-3-amine
將(2_氟苯基)聯胺鹽酸鹽(397毫克,2·439毫莫耳)及三 乙基胺(0.340毫升,2.439毫莫耳),在室溫下,加至授拌 中、溶解於乙醇(15毫升)之(3Ε)-4-胺基-4-(乙基氧一 二氟-3-丁烯-2-酮(中間物83, 406毫克,2.217毫莫耳)溶液 内’在氮氣層、96°C的溫度下,將混合物攪拌9小時,置 於至溫下過夜,另外,對(2_氟苯基)聯胺鹽酸鹽(357毫克, 2·2耄莫耳)加入在乙醇(1毫升)中之三乙基胺(〇·34〇毫升, 2·44笔莫耳),處理10分鐘(直到完全溶解),並將此溶液 加至别面之反應混合物,加熱迴流1小時(外部溫度 l〇(Ml〇 C),真空下除去溶劑,殘留物溶解於DCM,以水 -126- 200838508 洗滌後,再以DCM萃取(2x10毫升),合併的有機萃取層 被乾燥(Na2S〇4),過濾及在真空下濃縮,殘留物藉由石夕膠 管柱層析法純化(bi〇tage25M+管柱),以DCM 100%作為 溶離液,製得標題化合物,為一種淺橘色固體(97·6毫克, 16%) 〇(2_Fluorophenyl) hydrazine hydrochloride (397 mg, 2.439 mmol) and triethylamine (0.340 mL, 2.439 mmol) were added to the mixture at room temperature. Dissolved in (3 Ε)-4-amino-4-(ethyloxy-difluoro-3-buten-2-one (intermediate 83, 406 mg, 2.217 mmol) solution in ethanol (15 mL) 'The mixture was stirred for 9 hours at a temperature of 96 ° C in a nitrogen blanket, placed at room temperature overnight, and additionally, (2 - fluorophenyl) hydrazine hydrochloride (357 mg, 2·2 Torr) Adding triethylamine (〇·34〇ml, 2.44 moles) in ethanol (1 ml), treating for 10 minutes (until completely dissolved), and adding this solution to the reaction mixture, The mixture was heated under reflux for 1 hour (external temperature 〇 (Ml 〇 C), solvent was removed in vacuo, residue was dissolved in DCM, washed with water-126-200838508 and then extracted with DCM (2×10 mL). Drying (Na2S 〇4), EtOAc (EtOAc) (EtOAc) Kinds of light orange solid (97. 6 mg, 16%) square
lH NMR (400 MHz, CDC13): δ 3.79-3.96 (brs? 2Η) 5.92 (s,1Η) 7·26-7·31 (m,1Η) 7·31·7·37 (m,1Η) 7.45-7.54 (m, 1H) 7.53-7.62 (m,1H); UPLC_MS: 0.64 分鐘,246 [M+H]+。 【實施方式】 實例 實例 1 製備式(ΊΙΑ)的化厶物lH NMR (400 MHz, CDC13): δ 3.79-3.96 (brs? 2Η) 5.92 (s,1Η) 7·26-7·31 (m,1Η) 7·31·7·37 (m,1Η) 7.45- 7.54 (m, 1H) 7.53-7.62 (m, 1H); UPLC_MS: 0.64 min, 246 [M+H]+. [Embodiment] Example Example 1 Preparation of a chemical substance of the formula (ΊΙΑ)
15 實例1-1 L順式)3-茉基-8-αΓ4-Γ2-吡啶某嘁-2-臬1胺基}甲 基>1-氧雜-3-氮雜螺『4.51-癸烷-2-酮 將2-侧氧-3-苯基-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛 -127 - 200838508 (中間物,5, 0.277毫莫耳)及4-(2-吼唆基)-1,3_嗟唑-2-胺(9.9 耄克,0·056毫莫耳,Flu〇T〇chem)的混合物溶解於無水的 DCM (I·5晕升)後,攪拌1〇分鐘,再加入醋酸(15·86微升, 0.28耄莫耳)及聚苯乙烯-支撐的氰基氫硼化鈉(125毫克, 5 2·5-4·5微耄升/克載入,〜2.25 eq.)當量,反應以微波照 射,在110 C下加熱7分鐘兩次,將樹脂過濾,以dcm 洗滌,濾液被置於飽和的碳酸氫鈉水溶液與dcm間分配· 擊有機層㈣-種疏水的㈣龍在真訂濃縮,粗製品 (80毫克)藉由MDAP純化,製得此標題化合物(11 9毫克, ίο 11%,順式:反式為85:15的兩種異構物之混合物)。 實例1-2 噻唑 _2_ 甚 15 20 對溶解於二氯曱烷(1毫升、 ^ 毫克,㈣毫莫耳),在忙下)力之虱三異丙氧基化鈦⑽ 4·^ 加入至被攪拌中、溶解於 -虱曱43笔升)之(反式)_2_側氧 螺⑽癸燒各甲路(中間物7,n 4-(2-吡啶基)-1,3-噻唑-2-胺(44毫券__/兵耳)及 物,所得溶液被回溫至室溫,’ · ^旲耳)的混合 乙酸基_匕鈉(244毫克uf!V8小時’然後加入三 在室溫下攪拌2小時,再t飽:二滴的冰醋酸, 中止反應,加二«^(1()㉔^酸賴水溶液㈣升: 鈉水溶液以避免乳化且混合物έ:加二夠的虱乳化 物、、二由一種疏水的燒結物 -128- 200838508 (PhaseSep筒)過濾,以更多的二氯曱烷洗滌二遍,合併有 機層,減壓下濃縮,殘留物以二氯曱烷分散,留下白色固 體,將上澄液載入至一種NH管柱(12M,Biotage)以25-80% EtOAc/環己烷之梯度流洗,從此層析法溶離得之富含標題 5 化合物之劃分合併藉由分散分離得的固體,減壓下濃縮, 殘留物置於Si02上層析,以5-10% MeOH/二氯甲烷之梯 度流洗,製得標題化合物與(反式)-8-(羥基甲基)-3-苯基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮之混合物,將此混合物置於 一種SCX筒上純化,先以MeOH/二氯曱烷流洗,溶離出(反 ίο 式)-8-(羥基曱基)-3-苯基-1-氧雜-3-氮雜螺[4.5]癸烷_2_ 酮,再以溶解於MeOH/二氯甲烷之2MNH3溶離,製得此 標題化合物,為一種白色固體(63毫克)。 實例1-3 15 (反式V8-({「4-(6-甲基-2-吡啶基>1,3-噻唑-2-基1胺基}甲 基)-3-苯基-1-氣雜-3-氮雜螺「4.51癸烷-2-酮鹽酸鹽 * 將(反式)-8-({[4-(6-曱基-2-吼啶基)-1,3-噻唑-2-基]胺 基}甲基)-3-苯基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮(實例1-4, 染離鹼,0.038克,0.087毫莫耳)懸浮於乾燥的乙醚(1.5毫 20 升)後,加入溶在乙醚内之HC1 1Μ(0·105毫升,0.105毫莫 耳),形成沈澱,以乙醚分散,再於真空下乾燥,製得此 標題化合物,為黃色固體(37.9毫克,92.7%)。 實例1-415 Example 1-1 L cis) 3-methyl-8-αΓ4-Γ2-pyridine 嘁-2-臬1 amino}methyl>1-oxa-3-azaspiro"4.51-decane 2-keto 2-oxo-3-phenyl-1-oxa-3-azaspiro[4.5]decane-8-furaldehyde-127 - 200838508 (intermediate, 5, 0.277 mmol) And a mixture of 4-(2-mercapto)-1,3-oxazol-2-amine (9.9 g, 0·056 mmol, Flu〇T〇chem) dissolved in anhydrous DCM (I·5) After swelling, stir for 1 minute, then add acetic acid (15.86 μl, 0.28 Torr) and polystyrene-supported sodium cyanoborohydride (125 mg, 5 2·5-4·5) Microliters/g load, ~2.25 eq.) equivalent, the reaction was irradiated with microwave, heated at 110 C for 7 minutes twice, the resin was filtered, washed with dcm, and the filtrate was placed in saturated aqueous sodium hydrogencarbonate solution and dcm The title compound (11 9 mg, ίο 11%, cis: trans 85) was prepared by concentrating the organic layer (4) - a hydrophobic (4) dragon in a true concentrate, and the crude product (80 mg) was purified by MDAP. : a mixture of two isomers of 15). Example 1-2 Thiazole-2_ Very 15 20 pairs of dichlorodecane (1 ml, ^ mg, (tetra) millimolar), in the presence of force, triisopropoxide titanium (10) 4·^ Stirred, dissolved in -虱曱43 pen liters of (trans)_2_ side oxane (10) smoldering each road (intermediate 7, n 4-(2-pyridyl)-1,3-thiazole- 2-amine (44 vouchers __ / mils) and the resulting solution was warmed to room temperature, '· ^ 旲 ear) mixed acetate _ 匕 sodium (244 mg uf! V8 hours ' then added three in Stir at room temperature for 2 hours, then saturate: two drops of glacial acetic acid, stop the reaction, add two «^(1) 24 NaOH aqueous solution (four) liter: sodium aqueous solution to avoid emulsification and mixture έ: add two enough 虱The emulsified product was filtered from a hydrophobic sinter-128-200838508 (PhaseSep cartridge), washed twice with more dichloromethane, and the organic layer was combined, concentrated under reduced pressure, and the residue was dispersed with dichloromethane. , a white solid was left, and the supernatant was loaded onto a NH column (12M, Biotage) eluting with a gradient of 25-80% EtOAc / hexanes. Dividing by merging The resulting solid was concentrated under reduced pressure. EtOAcjjjjjjjjjj a mixture of -3-phenyl-1-oxa-3-azaspiro[4.5]nonan-2-one, which was purified on an SCX cartridge and washed with MeOH/dichloromethane. Dissolving (reversely)-8-(hydroxyindenyl)-3-phenyl-1-oxa-3-azaspiro[4.5]decane-2-one, dissolved in MeOH/dichloromethane The title compound was obtained as a white solid (63 mg). </ RTI> 1-3 15 (trans-V8-({4-(6-methyl-2-pyridyl)> 1,3-thiazole -2-yl 1amino}methyl)-3-phenyl-1-aza-3-azaspiro"4.51 decane-2-one hydrochloride* will (trans)-8-({[ 4-(6-Mercapto-2-oxaridinyl)-1,3-thiazol-2-yl]amino}methyl)-3-phenyl-1-oxa-3-azaspiro[4.5] The decane-2-one (Example 1-4, dye base, 0.038 g, 0.087 mmol) was suspended in dry diethyl ether (1.5 mL 20 L) and then added to EtOAc (1········ , 0.105 millimolar), formed a precipitate, dispersed in ether, and then The title compound was obtained as a yellow solid (37.9 mg, 92.7%).
200838508 吡啶基)-1.3-噻唑-2-基1胺基}甲 ^^^^ζίζΜΜ-3 -氮雜嫘『4.51癸烷-2-酮 5200838508 Pyridyl)-1.3-thiazol-2-yl1amino}methyl^^^^ζίζΜΜ-3 -azaindole "4.51 decane-2-one 5
10 15 將(反式)-2_側氧-3-苯基-1-氧雜-3-氮雜螺[4·5]癸烷-8-曱盤(以類似於製備中間物7之方式製備,〇·〇3克,0.116毫 莫耳)及4-(6-甲基-2-吡啶基)],3_噻唑-2-胺(製備法參考:10 15 (trans)-2_ side oxy-3-phenyl-1-oxa-3-azaspiro[4·5]decane-8-anthracene disk (in a manner similar to the preparation of intermediate 7) Preparation, 〇·〇3 g, 0.116 mmoles) and 4-(6-methyl-2-pyridyl)], 3_thiazol-2-amine (Preparation reference:
Journal of Medicinal & Pharmaceutical Chemistry, 1961, 35 561-6; 〇·〇24克,〇·127毫莫耳)溶解於乾燥DCm(2毫升)Journal of Medicinal & Pharmaceutical Chemistry, 1961, 35 561-6; 〇·〇 24g, 〇·127 mmoles) Dissolved in dry DCm (2 ml)
後’在室溫下攪拌〇·5小時,將混合物冷卻至並加入 洛解於^DCM (0.5毫升)之三異丙氧化氯鈦(〇〇55毫升, 0·232笔莫耳)溶液’令混合物慢慢地回溫至室溫並予以攪 拌過加入二滴的冰醋酸及三醋酸基氫硼化鈉(〇123克, 〇·58笔莫耳)’在室溫下攪拌2小時,混合物以π%稀釋, 加入NaOH 3〇%水溶液,以DCM萃取ρ X 毫升);各萃 取物被種相·分離注射過濾器,合併有機層,減壓 了濃縮丄所=留物藉由MDAp純化,合併含產物之劃 二”工下/辰、、、佰,以飽和的NaHCO3溶液鹼化,經DcM 萃取,其再通過—種相·分離注射過濾器,合併有機層, 在真空下濃縮,製得择 ^ 克78%)。 衣件铋喊化合物,為黃色泡沫物(39.2毫 20 實例1_-_5 (反式)-8-({「4-(3n 1 . 登烷-ϋϋΑ董 W化&物係,似於製備實例Μ之方式製備, -130- 200838508 使用(反式)-8-({[4-(3-曱基-2·-比啶基)-l,3-噻唑-2-基]胺基} 曱基)-3-苯基-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮(實例1-6, 游離鹼),製得此標題化合物,為帶黃色的固體(10.6毫克, 90 %)。 .5 實例1-6 (反式甲基-2-吡啶基VL3-噻唑-2-基1胺某}甲 基)-3-茉基-1-氣雜-3-氮雜螺「4.51癸烷-2-酮 此標題化合物係以類似於製備實例1-4之方式製備, 、1〇 將4·(6-曱基-2-σ比咬基)_ 1,3-σ·嗤-2-胺換成4-(3-甲基-2-ϋ比 啶基)-1,3-噻唑-2-胺(中間物13),製得此標題化合物,為 帶棕色之泡沫物(1〇·9毫克,21.6%)。 實例1_7 15 (反式)-3-(2_口比口定基)-8-({「4-(2-口比口定基)-1,3-17塞17坐-2-基1月安基} 曱基VI-氣雜-3-氮雜螺「4.51癸烷-2-酮二鹽酸鹽 ® 將三異丙氧化氯鈦(0.27毫升,1.13毫莫耳)溶解於5 毫升的DCM後,被加至溶解於15毫升的DCM之攪拌中 之4-(2-吼啶基)-1,3-噻唑-2-胺(100毫克,0.565毫莫耳)及 20 (反式)-2-侧氧-3-(2-吼啶基)-1-氧雜-3-氮雜螺[4.5]癸烷-8- 曱醛(中間物26, 133.7毫克,0.514毫莫耳)混合物内,混合 物變成黃色,在氮氣層内,室溫下繼續攪拌48小時,加 入三乙酸基氫硼化鈉(544毫克,2·57毫莫耳)及(0.029毫升, 0.514毫莫耳)的乙酸,粗製品被倒入至NaHC03的飽和溶 -131- 200838508 液(20毫升)内,以DCM萃取(50毫升),產生乳化液,加 入NaOH2M(3毫升),使用一種相分離管將溶液過濾,真 空下將有機層濃縮,粗製品使用一種Bi〇tage 25M NH管 柱純化,以DCM:Et20自1〇〇:〇至70:30溶離,製得(120 晕克,55%收量)的反式-3-(2-σ比咬基)-8-({[4-(2-12比口定 基)-1,3-噻唑-2-基]胺基}曱基)-1-氧雜-3-氮雜螺[4·5]癸烷 -2,酉同。 h-NMR (400 MHz,CDC13): δ 8·62_8·53 (1Η,m), 8·33-8·29 (1Η,m),8.24 (1Η,dt),7·91 (1Η,d),7·73-7·66 (2H,m),7·19-7·15 (1H,m),7.04-7.00 (1H,m),5·83-5·75 (1H,m), 5·30-5·27 (1H,m),3·98-4·03 (2H,m),3·22 (2H,t), 2·01_1·90 (4H,m)5 1·84·1·67 (3H,m),1·28-1·12 (2H,m) 〇 將反式_3-(2-u比啶基)-8-({[4-(2-σ比啶基)-l,3-噻唑-2、基] 胺基}曱基Η-氧雜冬氮雜螺[4.5]癸烷-2-酮(120毫克, 0.285毫莫耳)溶解於DCM(3毫升)後,一滴滴力α入至搜掉 中之溶解在乙醚中之1Μ鹽酸溶液⑴·626毫升,〇·626毫莫 耳)’在至溫下攪拌3〇分鐘,分出沈澱,分散於玢2〇,在 鼠乳流下濃縮,在4(rc下之高真空中乾燥,製得此標題 合物(132毫克,89%收量)。 實例1-8 基 噻唑 累『4.51 癸烷 杯題化δ物係以類似於製備實例1-7之方式製備, -132- 200838508 將(反式)_2_侧氧_3_(2“比唆基)小氧雜冬氮雜螺[ο]癸烷 -8-曱酸換成反式_3_(4_氟苯基)_2_侧氧小氧雜_3_氮雜螺 [4.5] 癸烧冬甲酸(中間物29, % 8毫克,〇 129毫莫耳),製 得此標題化合物,為—種帶棕色的泡沫(10.9毫克,21.叫 實例1-9 癸惊_2_酾睫鹼鹽 此標題化合物係以類似於製備實例1·7之方式製備, 將(反式)-2-侧氧_3_(2“比π定基)小氧雜_3•氮雜螺[4,习癸燒 各曱酸換成反式_3·(2_氟苯基)_2_ 雜 [4.5] 癸烧_8-曱別中間物埤%毫克,0.252毫莫耳 Μ·純化,製得此標題化合物(15毫克,12%)。)精由 15 20 實例1-10 --癸炫-2-酮驂g#鹽— 癸炫t 中2門1 氧_3 ·(3 ·吼°定基)小録^ 六说|甲%(中間物41,55 甲烷(4真斗、人,、五。見,11冤莫耳)溶解於二氯 _ 毛)’令部至〇c,然後加入三異丙氧化負# 毫升,M23毫莫耳),回溫至室溫,麟丙^^鈦(_ 酸基氫碉化鈉(224毫克丨〇57 *苴且、s 加入二乙 2.113毫料),⑽笔莫耳)及乙酸(〇.⑵毫升, )幻皿下擾拌4小時,現合物再置入於After stirring at room temperature for 5 hours, the mixture was cooled to and added to a solution of triisopropyl oxychloride (〇〇55 ml, 0·232 moles) dissolved in ^DCM (0.5 ml). The mixture was slowly warmed to room temperature and stirred. Two drops of glacial acetic acid and sodium triacetate hydride (123 g, 〇························ Diluted by π%, adding NaOH 3〇% aqueous solution, extracting ρ X ml with DCM); each extract was seeded and separated from the injection filter, the organic layer was combined, and the concentrated sputum was removed under reduced pressure. The residue was purified by MDAp and combined. The product containing the second line of "work" / Chen,,, 佰, alkalized with saturated NaHCO3 solution, extracted by DcM, and then through the seed phase separation filter, the organic layer, concentrated under vacuum, prepared Select gram 78%). The clothing screams compound, which is yellow foam (39.2 mils 20 Instances 1_-_5 (trans)-8-({"4-(3n 1 . Dessert - ϋϋΑ董W化 & The system was prepared as in the case of the preparation example, -130-200838508 using (trans)-8-({[4-(3-indolyl-2·-pyridinyl)-l,3-thiazole-2) - Amino} hydrazino)-3-phenyl-1-oxa-3-azaspiro[4.5]nonan-2-one (Example 1-6, free base) afforded the title compound Yellow solid (10.6 mg, 90%). .5 Examples 1-6 (trans methyl-2-pyridyl VL3-thiazol-2-yl 1 amine) methyl)-3-methyl-1- qi Hetero-3-azaspiro "4.51 decane-2-one. This title compound was prepared in a similar manner to the preparation of Examples 1-4, and 1 ((6-fluorenyl-2-σ ratio). _ 1,3-σ·嗤-2-amine was replaced by 4-(3-methyl-2-indolyl)-1,3-thiazol-2-amine (Intermediate 13) to give the title compound For brownish foam (1〇·9mg, 21.6%). Example 1_7 15 (trans)-3-(2_ mouth ratio base)-8-({"4-(2-mouth ratio)定定)-1,3-17 stopper 17 sit-2-yl January Anji} fluorenyl VI-gas-3-azane sulphate "4.51 decane-2-one dihydrochloride" oxidize triisopropyl After being dissolved in 5 ml of DCM, chlorotitanium (0.27 ml, 1.13 mmol) was added to 4-(2-acridinyl)-1,3-thiazole-2- dissolved in 15 ml of DCM. Amine (100 mg, 0.565 mmol) and 20 (trans)-2-oxo-3-(2-acridinyl)-1-oxa-3-aza snail [4.5] In a mixture of decane-8-furfural (intermediate 26, 133.7 mg, 0.514 mmol), the mixture turned yellow. Stirring was continued for 48 hours at room temperature in the nitrogen layer, and triacetate borohydride was added. Sodium (544 mg, 2.57 mmol) and (0.029 ml, 0.514 mmol) of acetic acid. The crude product was poured into a saturated solution of NaHCO. 50 ml), to produce an emulsion, add NaOH 2M (3 ml), filter the solution using a phase separation tube, concentrate the organic layer under vacuum, and purify the crude product using a Bi〇tage 25M NH column, with DCM:Et20 from 1 〇〇: 溶 to 70:30 dissolving, made (120 sag, 55% yield) of trans-3-(2-σ ratio bite)-8-({[4-(2-12 ratio) Stationary)-1,3-thiazol-2-yl]amino}indenyl)-1-oxa-3-azaspiro[4·5]nonane-2, the same. h-NMR (400 MHz, CDC13): δ 8·62_8·53 (1Η, m), 8·33-8·29 (1Η, m), 8.24 (1Η, dt), 7·91 (1Η, d) ,7·73-7·66 (2H,m),7·19-7·15 (1H,m),7.04-7.00 (1H,m),5·83-5·75 (1H,m), 5 ·30-5·27 (1H,m),3·98-4·03 (2H,m),3·22 (2H,t), 2·01_1·90 (4H,m)5 1·84·1 ·67 (3H,m),1·28-1·12 (2H,m) 〇 will be trans-3-(2-u-pyridyl)-8-({[4-(2-σ-pyridyl) )-l,3-thiazole-2,yl]amino}indolyl-oxaxanthroline[4.5]decane-2-one (120 mg, 0.285 mmol) dissolved in DCM (3 mL) After that, a drop of the force α was added to the 1 Μ hydrochloric acid solution (1)·626 ml, dissolved in diethyl ether, and stirred at the temperature for 3 minutes, and the precipitate was separated and dispersed in 玢2. The title compound (132 mg, 89% yield) was obtained by concentrating under a mouse emulsion and dried under high vacuum at 4 rc. Example 1-8 thiazolyl "4.51 decane cup title δ The system was prepared in a manner similar to the preparation of Examples 1-7, -132-200838508. (trans)_2_side oxygen_3_(2"-indenyl)oxyxanthroline[o]decane -8-decanoic acid was changed to trans-_3_(4_fluorophenyl)_2_side oxygen small oxygen heterozygous_3_azaspiro[4.5] 癸burning winter formic acid (intermediate 29, % 8 mg, 〇129 毫The title compound was obtained as a brownish foam (10.9 mg, 21. Example 1-9 癸 _2 酾 酾 酾 此 此 此 此 此 此 此 此 标题 标题 标题 标题 标题 标题 标题By way of preparation, (trans)-2-side oxygen_3_(2" than π-fixed) small oxa-3' aza snail [4, Xi 癸 曱 each 曱 acid replaced by trans _3 · (2_ Fluorophenyl)_2_hetero[4.5] 癸烧_8- 中间 中间 中间 毫克 毫克 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 -10 - 癸炫-2- 骖 骖 g# salt - 癸炫 t in the 2 door 1 oxygen _3 · (3 · 吼 ° fixed base) small record ^ six said | A% (intermediate 41,55 methane (4 true Bucket, person, five. See, 11 冤 Mo Er) dissolved in dichloro _ hair) 'order to 〇 c, then add triisopropyl oxidized minus # ml, M23 millimolar), warmed to room temperature,麟丙^^Titanium (_acid sodium hydroquinone sodium (224 mg 丨〇57 *苴, s added diethyl 2.13 milligrams), (10) penmo) and acetic acid (〇. (2) ml, ) Spoiled for 4 hours under the magic dish, and the present compound was placed again.
S -133- 200838508 DCM(20毫升),以NaHCCb萃取,粗製品以Bi〇tage spi 純化,於一種12M NH上,使用環己烷/Et〇Ac的混合物 為溶離液’以約65% EtOAc下溶離出(順式)冬(^比咬 基)-8-({[4-(2-吼咬基)-1,3-嗟嗤-2_基]胺基}甲基)小氧雜 5 -3-氮雜螺[4.5]癸烷-2-酮(57毫克)。 iH_NMR (400 MHz,CDC13)·· 8·61 (dq,1Η),8·57 (d, 1Η), 8·41 (d,1H),8·26 (dq,1H),7·94 (dt,1H),7·74 (dt,1H), ^ 737-7.32 (m? 1H)5 7.32 (s? 1H), 7.22-7.18 (m5 m)5 5.31 (brs! 1H), 3.78 (s,2H),3·33 (t,2H),2·23-1·25 (m,9H); ίο UPLC-MS: 0.48 分鐘,422 [M+H]+。 將其浴解於DCM’以1·1當量的溶解於乙鍵之HC1 處理’製得此標題化合物(67毫克)。 實例1-11 15 玉文基>8-((「4-(2-吡啶基嗟唑冬某]脸其} i基I"1-氧雜ϋ雜嫘「4·5]癸烷-2-酮^^鹽 此標題化合物係以類似於製備實例1β1〇之方式製 備,將(順式)-2-側氧_3_(3_吡啶基)_;!_氧雜氮雜螺 癸烧-8-曱則奐成(反式)冬侧氧_3_(3+定基)小氧雜各氮 20 雜螺[4.5]癸烷甲醛(中間物44,50毫克,〇192毫莫耳), 製得此標題化合物(4〇毫克),為一種黃色固體。 實例1-12 二^2_吡啶基>u_畫^孓基飞胺基丄^ •134- 200838508 基)3 乳雜癸烷_2•酮二鹽酴_ 此標題化合物係以類似於製備實例Ml之方式製 =,將4-(2-吼咬基H,3m胺換成4_(3_w定 嗟唾-2-胺(中間物47, 52 5亳克,〇 269毫莫耳),製 得此標題化合物(35毫克)。 實例 • 比啶篡 Vl,3-噻唑-2- 烷·2·酮二鹽酸鹽 1〇 將(反式)_3-(2·曱基_3_°比咬基)·2·側氧·1-氧雜-3-氮雜 螺[4.5]癸燒_8•甲搭(中間物5〇, 5〇毫克,ο】毫莫耳)、 4-(2:唆基 M,3h2,(32 3 ^,〇i82m^&5 異丙乳化氯鈦(0.087毫升,0.365亳莫耳)一起置入於二氯 甲烧(2毫升)後,在室溫下攪禅過夜,然後加入三乙酸基 15 氫硼化 =(193毫克,0.911毫莫耳)及乙酸(0.104毫升, I·823耄莫耳),在室溫下攪拌4小時,然後將混合物溶解 於DCM(20宅升),以飽和的价此〇3(2毫升)處理,再經 由一種分離管過濾,濃縮,製得粗製油質物(100毫克), 以Biotage SP1純化,在一種12+M KP-NH筒上進行,使 2〇 用環己烷及乙酸乙酯作為溶離液,製得(反式)-3-(2-甲基 -3比啶基)-8-({[4-(2-吼啶基)-l,3-噻唑-2-基]胺基}-甲 基)小氧雜-3-氮雜螺[4·5]癸烷-2-酮,為無色固體(60毫克)。 h-NMR (400 MHz,CDC13): 8·60 (dq,1Η),8.50 (dd, 1Η),7·91 (dt,1H),7·73 (dt,1H),7·60 (dd,1H),7·30 (s,1H),S-133-200838508 DCM (20 mL), extracted with NaHCCb, EtOAc EtOAc (EtOAc) Dissolved (cis) winter (^ than bite)-8-({[4-(2-吼)-1,3-1,3--2-yl]amino}methyl) small oxa 5 3-Azaspiro[4.5]decane-2-one (57 mg). iH_NMR (400 MHz, CDC13)·· 8·61 (dq,1Η),8·57 (d, 1Η), 8·41 (d,1H),8·26 (dq,1H),7·94 (dt ,1H),7·74 (dt,1H), ^ 737-7.32 (m? 1H)5 7.32 (s? 1H), 7.22-7.18 (m5 m)5 5.31 (brs! 1H), 3.78 (s,2H ), 3·33 (t, 2H), 2·23-1·25 (m, 9H); ίο UPLC-MS: 0.48 minutes, 422 [M+H]+. The title compound (67 mg) was obtained by dissolving EtOAc EtOAc EtOAc EtOAc EtOAc Example 1-11 15 Yuwenji>8-(("4-(2-pyridylcarbazole)] i-based I" 1-oxazepine "4·5] decane-2 -Ketone salt This title compound was prepared in a similar manner to the preparation of Example 1 ?1?, (cis)-2-yloxy_3_(3-pyridyl)-;!-oxaza-hydrazine-- 8-曱 奂 ( (trans) winter side oxygen _3_ (3 + fixed) small oxygen hetero nitrogen 20 snail [4.5] decane formaldehyde (intermediate 44, 50 mg, 〇 192 mM), system The title compound (4 mg) was obtained as a yellow solid. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2 keto distone 酴 _ This title compound is prepared in a manner similar to the preparation of Example M1, and 4-(2-bite-based H, 3m amine is replaced by 4_(3_w 嗟 嗟 -2--2-amine (intermediate) 47, 52 5 gram, 〇 269 mM, the title compound (35 mg) was obtained. Example: 比 篡 篡Vl, 3-thiazol-2-oxa-2 ketone dihydrochloride 1 〇 ( Trans) _3-(2·曱基_3_° ratio bite base)·2·Side oxygen·1-oxa-3-azaspiro[4.5]癸烧_8•甲搭 (Intermediate 5〇, 5 〇mg, ο] millimoles), 4-(2: fluorenyl M, 3h2, (32 3 ^, 〇i82m^&5 isopropyl emulsified chlorotitanium (0.087 ml, 0.365 Torr) was placed together in dichloromethane (2 ml). Stir at room temperature overnight, then add triacetate 15 borohydride = (193 mg, 0.911 mmol) and acetic acid (0.104 ml, I·823 耄 Mo), stir at room temperature for 4 hours, then The mixture was dissolved in DCM (20 liters), treated with 〇3 (2 mL), then filtered and concentrated to afford crude oil (100 mg), purified from Biotage SP1 The 12+M KP-NH cartridge was used to prepare (trans)-3-(2-methyl-3-pyridyl)-8-({2) with cyclohexane and ethyl acetate as the eluent. [4-(2-Acridine)-l,3-thiazol-2-yl]amino}-methyl)sodium oxa-3-azaspiro[4·5]nonan-2-one, Colorless solid (60 mg) h-NMR (400 MHz, CDC13): 8.60 (dq, 1 Η), 8.50 (dd, 1 Η), 7·91 (dt, 1H), 7·73 (dt, 1H) , 7·60 (dd, 1H), 7·30 (s, 1H),
-135- 200838508 7.25-7.17 (m,2H),3.73 (s,2H), 3.30 (m,2H),厶5 2·16-1·13 (m,9H)。 , 將其溶解於DCM(2毫升),與2Λ當量的溶解於乙醚 之1MHC1處理,製得為黃色固體之標題化合物(6〇亳克)。 .5 實例1-14 (反式)-8丄{『斗必-吡啶基)-i,j二噻皇基}甲^ 鲁 ,咬基)-,1二氧雜_3_氮雜螺『4·5]癸炫,-2_牲二鹽酸气 此標題化合物係以類似於製備實例之方式制 1〇 備,將(反式)_3-(2-曱基吡啶基)-2-侧氧-1氧雜雜 螺[4·5]癸烷-8-曱醛換成(反式)-2-侧氧·3-(5_^咬基)氧 雜-3·氮雜螺[4.5]癸烷-8-曱醛(中間物53, 2〇毫"克5^77 ^ 莫耳),製得此標題化合物,為一種黃色固體(13毫克)。 15 實例1-15 (順式)-8-甲_1-_3-(2-吡啶皋 V8-( 基胺基}甲基Id-氧雜-3-氮雜螺『4. 將三異丙氧化氯鈦(157毫克,〇·60毫莫耳)溶;於^毫 升的二氯甲烷後,被加至攪拌中、溶解於3毫升的二氯J; 20 烷中之4-(2-吡啶基卜1,3-噻唑胺(35·5毫克,〇·2〇毫莫耳) 及(順式)-8-甲基-2-側氧-3-(2-吡啶基氧雜_3_氮雜螺 [4.5]癸烷-8-甲醛(中間物58, 55毫克,〇·20毫莫耳)之溶液 中,混合物變成黃色,在氮氣層内,室溫下繼續攪掉&佔 小時,加入三乙酸基氫硼化鈉(212毫克,1〇〇2毫莫耳)及 -136 - 200838508 (0.011毫升,0·200毫莫耳)的乙酸,攪拌8小時,再加入 一些乙酸(0.011毫升,0·200毫莫耳),攪拌18小時,加第 三批量的乙酸(0.011毫升,0.200毫莫耳),再攪拌8小時, 加更多量的三乙酸基氫硼化鈉(106毫克,0.501毫莫耳)及 5 更多量的乙酸(0.011毫升,0.200毫莫耳),攪拌18小時, 以飽和的碳酸鉀溶液(10毫升)中止反應,加二氯甲烷(2〇 毫升)稀釋,並經由一種疏水的燒結物(PhaseSeperator筒) 過濾,以二氯曱烷(2 X 10毫升)洗滌,減壓下濃縮,殘留 物藉由Biotage層析純化(0-25%乙醚/二氯曱烷;25M管 1〇 柱),製得(順式)-8-曱基-3-(2-吡啶基)-8-({[4-(2-吡〇定 基)_1,3_噻唑-2-基]胺基}曱基)小氧雜-3-氮雜螺[4·5]癸烷 -2-酮(45毫克),為一種無色玻璃質物。 h-NMR (400 ΜΗζ,丙酮-dB): δ 8·53 (1Η,d)5 8·33 (1Η,d),8·19 (1Η,d),8·00 (1Η,d),7·77-7·83 (2Η,m),7·29 15 (1H,s),7·22 (1H,dd),7·08 (1H,dd),6·90 (1H,t),4.00 (2H, s)5 3·48 (2H,d),2·00-2·09 (2H,m),1·94 (2H,td),1·84 (2H, 籲 td),1·51 (2H,dt),1.13 (3H,s); UPLC-MS·· 0·62 分鐘,436 [M+H]+5 218 [M+2H]2+ 將在乙醚中之L0MHC1 (0.296毫升,0.296毫莫耳)加 2〇 至攪拌中、溶解在二氯曱烷之(順式)-8-甲基呢唆 基)_8-({[4-(2-吼啶基)-1,3·噻唑-2-基]胺基}甲基)七氧雜 -3-氮雜螺[4.5]癸烷-2-酮(43毫克,0·099毫莫耳)溶液,立 即有白色沈殿形成,加入足量之甲醇以形成均質的溶液, 攪拌30分鐘,其間有白色沈澱自黃色溶液中沈澱下來, •137- 200838508 將混合物過濾,以乙醚洗滌濾餅(2x5毫升),再在的^的 真空下乾燥4小時,製得50毫克的黃色固體,溶解於曱 醇(1毫升),濃縮三遍,再於6(rc的真空下乾燥6小時, 製得標題化合物(49毫克),為一種黃色固體。 實例1-16 定基 V8-(U4-(2-吡啶基 V丄ρ塞 n 基甲基氮雜嫘[4.51癸-烧_2_酮鹽酸贛 將二異丙氧化氯鈦(0084毫升,0.350毫莫耳)溶解於 二氯甲烷(0.5毫升)後,在室溫下,加至裝有溶解於二氯曱 烧(2毫升)中,被攪拌著的(反式)-8_甲基_2_側氧_3_(2_吼啶 基)-1_氧雜-3-氮雜螺[4·5]癸烷曱醛(中間物59, 32毫克, ο·ιπ毫莫耳)及4_(2_吡啶基噻唑_2_胺(2〇 67毫克, 0·117耄莫耳)的混合物之玻璃瓶内,所得的黃色混合物被 ,拌過夜(〜18小時),加入更多的三異丙氧化氯鈦(0.041 毛升,0.175耄莫耳),再攙拌24小時,加入三乙酸基氫棚 化鈉(124耄克,0.583毫莫耳)及乙酸(〇·〇2〇毫升,〇 35〇毫 莫耳)’攪拌6小時,再添加乙酸(〇〇2〇毫升,〇.35〇毫莫 耳)’攪拌過夜(〜18小時),以二氯甲烷(5毫升)稀釋後, 加入飽和的碳酸鉀溶液(3亳升)中止反應,加入足夠的水 使水心液層可移動至有機層之上,再經由一種疏水的燒結 ^(PhaseSeperator筒)過濾,以更多的二氯甲烷洗滌(3χ5 笔升)’浪纟倍有機層並經由Bi〇tage將殘留物純化兩遍(第 一次純化使用1〇〇%CH2C12;i2MNH管柱;第二次純化使 -138- 200838508 用20-50%之EtOAc/環己烷;12M NH2管柱),製得(反 式)-8-曱基-3·(2·σΛσ定基)-8-( 胺基}曱基)小氧雜-3-氮雜螺[4.5]癸烷-2-1同(24毫克),為 一種白色泡沫物。 5 h-NMR (400 MHz,CDC13): δ 8.61 (1H,d),8·33-8 36 (1Η,m),8·27 (1Η,d),7·92 (1Η,d),7.69簡7·78 (2Η,m),7·3〇 (1H,s),7·17-7·22 (1H,m),7·05 (1H,dd)5 5·24 (1H,brt), 4.04 (2H, s),3·30 (2H,d)5 1·97-2·08 (2H,m)5 1·83-1·94 (2H, ’ m),1·65_1·80 (2H,m),1·52-1·64 (2H,m)5 1·12 (3H,s): 10 UPLC-MS: 0.63 分鐘,436 [M+H]+,218 [M+2H]2+ 將溶解在乙醚中之LOM HC1(0.152毫升,〇·ΐ52毫莫 耳),在室溫下,加至在玻璃管内、攪拌中、溶解於二氯 甲烷(2毫升)及曱醇(0·1毫升)中之(反式)-8-曱基|(2^比唆 基)1({[4-(2-吼啶基)_1,3_噻唑-2-基]胺基}甲基)小氧雜 I5 -3-氮雜螺[4.5]癸烷-2-酮(22毫克,0.051毫莫耳)溶液,擾 拌1小時後,減壓下除去揮發物,殘留物分散於乙醚(4毫 • 升),過濾,以更多的乙醚(2 X 2毫升)洗滌濾餅,以集黃 色固體,在60°C下減壓乾燥3小時,製得標題化合物(21 毫克),為一種黃色固體。 20 實例1-17 (^式)-3-(6-曱基-2-吡啶基)-8_({「4-(2-吡啶基)'1,3-嚓崦_2-基1胺基}甲基VI-氧雜-3-氮雜螺[4.51癸烷-2-酮 此標題化合物係以類似於製備實例M3之方式製 -139- 200838508 備,將(反式)-3-(2-曱基-3-吡啶基)-2-側氧-1-氧雜-3-氮雜 螺[4.5]癸烷-8-曱醛換成(反式)-3-(6-曱基-2-吼啶基)-2-側 氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛(中間物62, 24毫克, 0.087毫莫耳),製得標題化合物,為一種黃色固體(6毫克)。 5 實例1-18 (反式)-3-(6-氟-2-吡啶基V8-({「4-(2-吡啶基)-1,3-噻唑-2-基1 胺基丨甲基)-1-氣雜-3-氮雜嫘「4.51癸烷-2-酮 * 此標題化合物係以類似於製備實例1-13之方式製 1〇 備,將(反式)-3_(2-曱基-3-吡啶基)-2-侧氧-1-氧雜-3-氮雜 螺[4.5]癸烷-8-曱醛換成(反式)-3-(6-氟-2-吡啶基)-2-侧氧 -1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛(中間物64, 21毫克, 0.075毫莫耳),製得此標題化合物(15·4毫克;29%)。 15 實例1-19 (反式)_3 _(2_ 0比g定基)_8_( 外匕口定基)_ 1,3 _ 口塞口坐-2-基1月安 • 基}乙基M-氧雜-3-氮雜螺「4.51癸烷-2-酮二鹽酸鹽 於-78°C的氮俘層下,對攪拌中、溶解在THF(5毫升) 之曱基溴化鎂(3M溶在乙醚之溶液)(0.309毫升,0.928毫 20 莫耳),滴入溶解在四氫吱喃(10毫升)之(反 式)-8-(1Η-1,2,3_苯并三唑-1-基{[4-(2-啦啶基)-1,3-噻唑-2-基]胺基}曱基)-3-(2-。比啶基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮(中間物65, 200毫克,0.371毫莫耳)之溶液内,將混合 物攪拌30分鐘,歷經45分鐘使混合物回溫至室溫,攪拌 200838508 2小時,倒至水中(20毫升),以乙酸乙酯(15毫升)萃取一 遍,合併有機層,經水洗滌,經由一種疏水的燒結物 (Phase-Sep膜)過濾並在真空下被濃縮,粗鼠品先在—種 NH管柱上純化,以二氯甲烷/乙醚(1:〇至1〇:1梯度)溶離, 5 再於一種矽膠管柱上,以二氯甲烷/甲醇/三乙基胺(1:〇.〇 至95:5+1滴/50毫升三乙基胺)溶離,合併含產品之割八 被轉變成HC1鹽’將固體溶解於甲醇,藉由sex離子六 _ 換層析法純化,以i)甲醇,ii)2M氨水-曱醇溶離,將鹼= 劃分置於真空下濃縮’製得(反式)_3_(2_定 10 基比啶基)-1,3-噻唑-2-基]胺基}乙基广丨氧雜 -3-氮雜螺[4.5]癸烷-2-酮(19.0毫克),為一種澄清粘稠^由^ 物。 、 kNMR (400 MHz,CDC13)·· δ 8·60 (1H,d),8.34 (1H d),8·27 (1Η,d),7·92 (1Η,d),7·68-7·76 (2Η,m),7·29 (1Η 15 d),7·19 (1H,dd),7·04 (1H,dd),5·14 (1H,d),4·05 (2H,s), 3·50-3·60 (1H,m),1·75-2·1〇 (6H,m),1.55-1.67 (1H,m), 1·23-1·42 (2H,m),1·29 (3H,s)。 將其溶解於二氯甲烷(1毫升)並加入HC1(1M,溶解於 乙醚)(〇·113毫升,〇·113毫莫耳),使之靜置1〇分鐘後, 2〇 在氮氣流中,於4(rc下濃縮,殘留物在4〇〇c的真空下乾 燥,製得標題化合物(2〇 〇毫克),為一種黃色粉末物。 實例1-20 G良式)_8_丄吡啶某VL3·噻唑-2-基1胺 -141 - 200838508 基V3-(2-吡啶基)-1-氣雜-3-氮雜嫘『4.51癸烷-2-酮 此標題化合物係以類似於製備實例1-13之方式製 備,將(反式)-3-(2-曱基-3-吼啶基)-2-侧氧-1-氧雜-3-氮雜 螺[4.5]癸烷-8-甲醛換成(反式)-2-側氧-3-(2-吡啶基)-1-氧 5 雜-3-氮雜螺[4.5]癸烷I曱醛(此可根據製備中間物26之 方式製備,133毫克,0.512毫莫耳)且將4-(2-吡啶基)-1,3-噻唑-2-胺換成5-氟-4-(2-吡啶基)-1,3-噻唑-2-胺(中間物66, 100毫克,0.512毫莫耳),製得標題化合物(31毫克),為略 •帶黃色之固體。 10 所有這些分析數據被出示於下面表1-1中且其中R、 Z、Ζι、Αι 及 B 為:-135- 200838508 7.25-7.17 (m, 2H), 3.73 (s, 2H), 3.30 (m, 2H), 厶 5 2·16-1·13 (m, 9H). The title compound (6 g) was obtained as a yellow solid. .5 Example 1-14 (trans)-8丄{『斗必-pyridyl)-i,jdithiametic}A^ Lu, bite base)-,1 dioxa _3_aza snail 4·5] 癸 Hyun, -2_ oxalic acid gas This title compound is prepared in a manner similar to the preparation example, and (trans)_3-(2-mercaptopyridyl)-2-side oxygen -1 oxaspiro[4·5]decane-8-furaldehyde is replaced by (trans)-2-side oxygen·3-(5_^biti)oxa-3-azaspiro[4.5]癸The title compound was obtained as a yellow solid (yield: 13 mg). 15 Example 1-15 (cis)-8-methyl-1-_3-(2-pyridinium V8-(ylamino)methylId-oxa-3-azaspiro"4. Oxidation of triisopropyl Chlorotitanium (157 mg, 〇60 mmol) is dissolved in dichloromethane (2 ml), added to stirring, dissolved in 3 ml of dichloro J; 4-(2-pyridyl) in 20 alkane 1,3-thiazolylamine (35·5 mg, 〇·2〇 mmol) and (cis)-8-methyl-2-oxo-3-(2-pyridyloxa)__nitrogen In a solution of snail [4.5] decane-8-formaldehyde (intermediate 58, 55 mg, 〇 20 mmol), the mixture turned yellow, and in the nitrogen layer, stirring was continued at room temperature for an hour. Add sodium triacetate borohydride (212 mg, 1 2 2 mmol) and -136 - 200838508 (0.011 mL, 0.200 mmol) of acetic acid, stir for 8 hours, then add some acetic acid (0.011 ml) , 0. 200 mmol, stirring for 18 hours, adding a third batch of acetic acid (0.011 ml, 0.200 mmol), stirring for another 8 hours, adding more sodium triacetoxyborohydride (106 mg, 0.501 mmol) and 5 more acetic acid (0.011 ml, 0.200 mmol), stirred for 18 hours. The reaction was quenched with saturated potassium carbonate solution (10 mL), diluted with dichloromethane (2 mL) and filtered thru a s. Concentration by pressing, the residue was purified by Biotage chromatography (0-25% diethyl ether / dichloromethane; 25 M tube 1 column) to give (cis)-8-mercapto-3-(2-pyridyl) )-8-({[4-(2-pyridinyl)_1,3_thiazol-2-yl]amino}indenyl)sodium oxa-3-azaspiro[4·5]nonane-2 a ketone (45 mg) as a colorless glassy material. h-NMR (400 ΜΗζ, acetone-dB): δ 8·53 (1Η,d)5 8·33 (1Η,d),8·19 (1Η, d), 8·00 (1Η, d), 7·77-7·83 (2Η, m), 7·29 15 (1H, s), 7·22 (1H, dd), 7·08 (1H, Dd),6·90 (1H,t), 4.00 (2H, s)5 3·48 (2H,d),2·00-2·09 (2H,m),1·94 (2H,td), 1·84 (2H, ttd), 1·51 (2H, dt), 1.13 (3H, s); UPLC-MS·· 0·62 minutes, 436 [M+H]+5 218 [M+2H] 2+ Add 2 〇 of L0MHC1 (0.296 ml, 0.296 mmol) in diethyl ether to the mixture and dissolve in chloroformane (cis)-8-A 88-({[4-(2-Acridine)-1,3.thiazol-2-yl]amino}methyl)heptaoxa-3-azaspiro[4.5]decane a solution of 2-ketone (43 mg, 0. 099 mmol) immediately formed with a white smear, and a sufficient amount of methanol was added to form a homogeneous solution, which was stirred for 30 minutes, during which a white precipitate precipitated from the yellow solution. 137- 200838508 The mixture was filtered, and the filter cake was washed with diethyl ether (2×5 ml) and dried under vacuum for 4 hours to yield 50 mg of a yellow solid, dissolved in decyl alcohol (1 ml) and concentrated three times. The title compound (49 mg) was obtained as a yellow solid. Example 1-16 Stationary V8-(U4-(2-pyridyl V丄ρ塞nylmethylazaindene [4.51癸-burning 2_one guanidine hydrochloride 赣 titanium diisopropyloxide oxychloride (0084 ml, 0.350 m) After being dissolved in dichloromethane (0.5 ml), it was added to a mixture of (trans)-8-methyl-2 dissolved in dichlorohydrazine (2 ml) at room temperature. _ Side Oxygen_3_(2_Acridine)-1_oxa-3-azaspiro[4·5]decanefurfural (intermediate 59, 32 mg, ο·ιπ millimol) and 4_( In a glass vial of a mixture of 2_pyridylthiazole-2-amine (2〇67 mg, 0·117 mmol), the resulting yellow mixture was stirred overnight (~18 hours) and more triisopropyl was added. Titanium oxide oxide (0.041 liters, 0.175 Torr), and then mash for 24 hours, add triacetate hydrogenated sodium (124 gram, 0.583 mmol) and acetic acid (〇·〇2 〇 ml, 〇35 〇 莫 )) 'Stirring for 6 hours, then add acetic acid (〇〇 2 〇 ml, 〇. 35 〇 millimolar) 'Stir overnight (~18 hours), dilute with dichloromethane (5 ml), add saturation Potassium carbonate solution (3 liters) to stop the reaction, add enough water to make the water It can be moved over the organic layer, filtered through a hydrophobic sintering membrane (PhaseSeperator cartridge), washed with more dichloromethane (3χ5 liters), and the residue is purified by Bi〇tage. Throughout (first purification using 1% CH2C12; i2MNH column; second purification using -138-200838508 with 20-50% EtOAc/cyclohexane; 12M NH2 column), made (trans) -8-mercapto-3((2·σΛσ定)-8-(amino}indenyl)oxyx-3-azaspiro[4.5]decane-2-1 with (24 mg) as a kind White foam. 5 h-NMR (400 MHz, CDC13): δ 8.61 (1H,d),8·33-8 36 (1Η,m),8·27 (1Η,d),7·92 (1Η, d), 7.69 Jan. 7.78 (2Η, m), 7·3〇 (1H, s), 7·17-7·22 (1H, m), 7·05 (1H, dd) 5 5·24 ( 1H, brt), 4.04 (2H, s), 3·30 (2H, d) 5 1·97-2·08 (2H, m) 5 1·83-1·94 (2H, ' m), 1· 65_1·80 (2H,m),1·52-1·64 (2H,m)5 1·12 (3H,s): 10 UPLC-MS: 0.63 minutes, 436 [M+H]+,218 [M +2H]2+ LOM HC1 (0.152 ml, 〇·ΐ 52 mmol) dissolved in ether, added to the glass tube at room temperature (dissolved), dissolved in dichloromethane (2 ml) and decyl alcohol (0.1 ml) (trans)-8-fluorenyl | (2^ than mercapto) 1 ({[4-(2- Acridine)_1,3_thiazol-2-yl]amino}methyl)oxyxa I5-3-azaspiro[4.5]nonan-2-one (22 mg, 0.051 mmol), After 1 hour of stirring, the volatiles were removed under reduced pressure and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjj The title compound (21 mg) was obtained as a yellow solid. 20 Example 1-17 (Formula)-3-(6-Mercapto-2-pyridyl)-8_({"4-(2-pyridyl)'1,3-嚓崦_2-yl 1 Amino }Methyl VI-oxa-3-azaspiro[4.51 decane-2-one This title compound was prepared in a manner similar to the preparation of Example M3 - 139-200838508, (trans)-3-(2 -mercapto-3-pyridyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-furaldehyde is replaced by (trans)-3-(6-fluorenyl- 2-oxaridinyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-furaldehyde (Intermediate 62, 24 mg, 0.087 mmol) afforded title compound , a yellow solid (6 mg). 5 Example 1-18 (trans)-3-(6-fluoro-2-pyridyl V8-({"4-(2-pyridyl)-1,3-thiazole -2-yl 1 amino hydrazinylmethyl)-1-oxa-3-azaindole "4.51 decane-2-one* This title compound was prepared in a manner similar to the preparation of Examples 1-13. Replace (trans)-3_(2-mercapto-3-pyridyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-furfural with (trans) -3-(6-fluoro-2-pyridyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-furfural (intermediate 64, 21 mg, 0.075 mmol) Ear), made the title compound 15·4 mg; 29%). 15 Example 1-19 (trans)_3 _(2_0 ratio g base)_8_(outer mouth base)_ 1,3 _ mouth mouth sitting-2-base January • Ethyl M-oxa-3-azaspane "4.51 decane-2-one dihydrochloride" under a nitrogen trap at -78 ° C, stirred and dissolved in THF (5 mL) Mercapto-magnesium bromide (3M solution in diethyl ether) (0.309 ml, 0.928 mmol 20 mol), and added dropwise (trans)-8-(1Η-1,2) dissolved in tetrahydrofuran (10 ml) , 3_benzotriazol-1-yl{[4-(2-oxaridinyl)-1,3-thiazol-2-yl]amino}indolyl)-3-(2-.pyridyl) In a solution of 1-oxa-3-azaspiro[4.5]nonan-2-one (intermediate 65, 200 mg, 0.371 mmol), the mixture was stirred for 30 minutes and the mixture was allowed to warm for 45 minutes. The mixture was stirred at room temperature for 2 hours, poured into water (20 ml), and extracted with ethyl acetate (15 ml). The organic layer was combined, washed with water, and filtered through a hydrophobic sinter (Phase-Sep film) Concentrated under vacuum, the crude mouse is first purified on a NH column, eluted with dichloromethane/diethyl ether (1: 〇 to 1 〇:1 gradient), 5 and then On the hose column, it was dissolved in dichloromethane/methanol/triethylamine (1: 〇.〇 to 95:5 +1 drops/50 ml of triethylamine), and the combined cuts containing the product were converted into HCl salts. The solid was dissolved in methanol, purified by sex ion chromatography, i) methanol, ii) 2M aqueous ammonia-nonanol, and the base = partitioned under vacuum to make 'trans (trans)_3_( 2_定10 benzylidene)-1,3-thiazol-2-yl]amino}ethyl fluorenoxa-3-azaspiro[4.5]decane-2-one (19.0 mg), A clarified viscous ^^^. kNMR (400 MHz, CDC13)·· δ 8·60 (1H,d), 8.34 (1H d),8·27 (1Η,d),7·92 (1Η,d),7·68-7· 76 (2Η,m),7·29 (1Η15 d),7·19 (1H,dd),7·04 (1H,dd),5·14 (1H,d),4·05 (2H,s ), 3·50-3·60 (1H, m), 1·75-2·1〇(6H,m), 1.55-1.67 (1H,m), 1·23-1·42 (2H,m) ,1·29 (3H, s). This was dissolved in dichloromethane (1 ml) and added with HCl (1 M, dissolved in diethyl ether) (〇·113 mL, 〇·113 mmol), allowed to stand for 1 Torr, The residue was concentrated under EtOAc (4 mL). EtOAcjjjjjjjjj VL3·thiazol-2-yl 1amine-141 - 200838508 base V3-(2-pyridyl)-1-aza-3-azaindole "4.51 decane-2-one. This title compound is similar to the preparation example. Prepared by way of 1-13, (trans)-3-(2-indolyl-3-acridinyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8 - Formaldehyde is replaced by (trans)-2-oxo-3-(2-pyridyl)-1-oxo-5oxa-3-azaspiro[4.5]decane-furfural (this can be prepared according to the intermediate 26 Prepared by 133 mg, 0.512 mmol, and 4-(2-pyridyl)-1,3-thiazol-2-amine was replaced by 5-fluoro-4-(2-pyridyl)-1,3 - thiazol-2-amine (Intermediate 66, 100 mg, 0.512 mmol). 10 All of these analytical data are presented in Table 1-1 below and where R, Z, Ζι, Αι, and B are:
-142- f ^ ) 200838508-142- f ^ ) 200838508
ih合綠 z Zt At «δ 分#數據 ' . * 1-1 Ph GHz H % umr (sm mz, cogw: 5 zmb (1H, ά% ?,ΒΦ7Μ {1H, m)f 7J8*7.T0 (tH, m)t ?M-7.m {2Ht m)t ?A2^7M Pi 7.23 (,s), 720412 {2H, m), BM (1He s), 3.82-3,73 pi, m), 3J3·浦(1H. m>· SJ2424 PHjb), 2.23*2.00 (3H m), 1.^176 <4H m>; Ph 0¾ H mn (4¾} MHz, CDCb); δ Bm (1H.CI}, im {ia Φ,7,74 (1Hf dl}s 7,68 (2H, d)8 Z40 (2H, 7*31 {1Hf s% 7^0 (1H, ddcQf 7,15 (1Ht I), 5.23 (1H, % 3.B2 <m s), 3.S1 {2H, % 2M (4H, m)f 1,00 (3H, m), m); itl/2腿:421_侧寺· • 1-3 Fh 0¾ , U ότ m mm (boo mzt Bmso-ά): δ 5.20 (2H, br s), am (1H, br s)r 7J8 (1H brs), Τ.ββ (2 Η Φ,7,51 (1H br s)f 7.3δ (2H, dc〇, T.10 (1Ht 3.^ 3,98 (2H, m), 3,17*3.32 PH m>t 2M (3M, s)f f .90-Z02 (2H, m% ίΜΰΑΜ (2H, iti}, 1·游 1J7 (3Η· _ 1_飢31 {H.nii); HFLC-MS 2i 2Μ min, m& 4S5 |Μ+ΗΙ+ 14 Ph CHa H Λ Ή NMR {400 ΜΗζ, CDCfe): ^ 7.55-7.73 {4Hfc m)t 7.3B-T,44 {2H, in), T.3Q-7.33 (1H, m), 7.0^7,19 (2H, m), SJ3 (2H, s), 3J7-3.34 (2H Q, 2,^2 (s, S H>, 1.98-2J2 (4Ht m), 17^ 1.§7 (3 H, m)t f ^1*1,34 (3H, m); HPIG44S1:1‘84m【n,論 4筇 1-5 Ph 0¾ H o ^ ^ {i〇〇 MHz, DMSO^: δ S,S1^ 8.7D (1H, m}f 8.^8.44 {2H, br. s), 7,65-7,81 (1H, br s)f 7,52-7,65 (SH, ni), ?.^7,43 pH, m)f 7,06^7,18 (1Ht m), (2H* br s)f 3.32^3.40 <2H, m》》Z&l (3HS 砵 1.58^04 (7H im), 130-160 (2Η,ϊη); HPLOMS a; 2,09 rnri, mfz 43St 1名 Ph CH2 H •^VWW o % 、HN_(4l_z,CDCb}:5 8.4& BJ6 (1H, m), 7.62-7 J5 (3H, in}, 7J4-7M (2Ht m>f 7,11-7.23 (2H, m)f 6.91 {1H, 4 S洛3 C2H, s)t 327435 深H, !), 2.57 (SHs S), 1JS-2.11 (4H, ii), 120-140 m)^ 〇 7S-0.95 ¢2¾ m); HPLC-MS t: 1,75 mh, m&435 ί-7 \o 0¾ H * 1H HMR (405 MHz, DySOS): δ 8, 61 (! H, d), S37 (t H d)f 8.10.7*97 {4 K m), 7.87-7,80 (1 H, td), 7M {1 Hf bns.)t 7 JO (1 H, br,s4 7,15 (1 Hf dd), 4¾ p H, $>, 3,51-327 <3 Η, Hfl), 199 (2 H, <f), 1,85 (4 H, dd), 1JS-| 162 (SH, m), 1.^1,21 <2 H( m); I UPLG^Staaamin^ZZf^HI^ -143- 200838508 1名 \ζΤ CHe H ^Vl ih mm ^ tmzf mm δ ns-1J1 (m, 2 H) umm (mf 1 1.S5* f J4 (td, 2 H) 1.9^2.09 {m, 4 H) 3,30 (t 2 ^ 3 JB (¾ 2 H) S.23 fsf 1 H), 7.08 <t( Z H) ?ja*?.2t (mf 1 H) 73<3 (表 1 H) 7JS Cd4 2 H) 7.73 H) 7*80 換 1Η}8·§3 紙1 埽; UPLC-撇0應論,439陳, 1-9 \φ F Chfe H ί^ΧΗ iS 涵R,戰 MeOH^4) δ 123.1,35 (m, 2 H) UMi4 (m, 3 Η) tm-2m (mf 2H) 2Μ-2ΛΒ (m, 2 H) BM 4 H| 3.36 {s, 2 H) ¾ 2 H) 3.92 a Η) T,18-7,23 {ibs 2 H) 7,31-7.40 (m, 1 H) 7 J2 ft 1 H) 7.80-7.92 (mt 2 H) 8.38-S.S4 (m, 2 Hj 837 紙1« UPLC4M: 0.62 mifu 4m mm^ 1-10 〇Ht H 1H mmim MHI, DMSQ-m): δ sjo^s,鉍 c<4 ih》, sj+aso 紙 1H), 8,404.30 (m, 4H), 7 J2*7 J7 {ib, 3H), aso {s, 3J7 φΐΒ, 1H)t (mB 9H); HPLOMS; 133 mia 422 1-11 Λ ch2 H ^Vi Ή NMR (400 MHz, DMSO-cBj; δ S.95 Ρ, 1H), 8,67 (A Bm m \ 1H># 840-5.23 (m% 3H), 7SS-7MZ (in, 3H)f 4,03 ($, 2H)4 3.34 {hr s, 2H)f 2.07^82(10,9H>; UPLC-MS: 0.47 mlns 422 mm^ t»12 νΟ 0¾ H ^ mm {400 MHz, oiso^ds): δ 8.94 {d, 1H), 8,5^8.48 (m, 2H), 8,35 (rn, 1H)a 7JS-7.8& (ιτϊ* IH), ?.79-7M (m31H)f 7J8-T.S2 (m, 1H), 7^3 (ss 1H), 4Λ2 (s, 2¾ 3J1 (m, 2H), 讓韻7 ㈣1J4-117 (in·靴 UPLOIWS: ChS4 44GM+_" 1-13 ν9 CHi H Ή _R 000 祖 _S0^: δ 8.69-S.^ (ms 2¾ 8.36-8.22 {mt 3H), 7,87-7,81 {m, 1H)f 7,74-7.64 ¢1¾ 2H)f 0r 2H), 3J2 (br s, 2H)f 2,14-lSS (m# 7H)f 1,27-1,13 {m, 2H); UPL_&陳眺436賺胁 1-14 CHi H 卿 MHz, DMSO_: δ 9M 2H)t aS4 {s, 1H3, BMQSM (tis, 1H), 8.35-8,24 (mt 2H), 7.S2 (m, 1H), 7,67 (m, 1¾ 400 (% 2HX 3,33 (br s, 2H)a 2.08^1^ (m, 7H), 1J2-11S_b2H}; UPLC 撒 0·δ〇 min* 423顧令 HI, 1-1S 0¾ :m 1H-NMR (400 MHz, DMSOd^; § SJ1 (1H, d), 8.31-8,58 (4Ht m), Bm (IH, d), 8.0S {1H, s)t TJ3^7,89 (2Ht m), 7.14 (1H, dd), 3.95 {2Mf s), 343 (2H, S)t 1.774.S7 <4Hf m)f 1MA72 pH, m), 1.33^147 (2H, m), 1,04 (3H, 參 UPLC-MS; QMZ irtn, 436 2t8,麵. -144- 200838508Ih合绿z Zt At «δ分#数据' . * 1-1 Ph GHz H % umr (sm mz, cogw: 5 zmb (1H, ά% ?, ΒΦ7Μ {1H, m)f 7J8*7.T0 ( tH, m)t ?M-7.m {2Ht m)t ?A2^7M Pi 7.23 (,s), 720412 {2H, m), BM (1He s), 3.82-3,73 pi, m), 3J3·Pu (1H. m>·SJ2424 PHjb), 2.23*2.00 (3H m), 1.^176 <4H m>; Ph 03⁄4 H mn (43⁄4} MHz, CDCb); δ Bm (1H.CI} , im {ia Φ,7,74 (1Hf dl}s 7,68 (2H, d)8 Z40 (2H, 7*31 {1Hf s% 7^0 (1H, ddcQf 7,15 (1Ht I), 5.23 (1H, % 3.B2 <ms), 3.S1 {2H, % 2M (4H, m)f 1,00 (3H, m), m); itl/2 legs: 421_ side temple · • 1 -3 Fh 03⁄4 , U ότ m mm (boo mzt Bmso-ά): δ 5.20 (2H, br s), am (1H, br s)r 7J8 (1H brs), Τ.ββ (2 Η Φ,7, 51 (1H br s)f 7.3δ (2H, dc〇, T.10 (1Ht 3.^ 3,98 (2H, m), 3,17*3.32 PH m>t 2M (3M, s)ff .90 -Z02 (2H, m% ίΜΰΑΜ (2H, iti}, 1·游1J7 (3Η· _ 1_饥31 {H.nii); HFLC-MS 2i 2Μ min, m& 4S5 |Μ+ΗΙ+ 14 Ph CHa H Λ NMR NMR {400 ΜΗζ, CDCfe): ^ 7.55-7.73 {4Hfc m)t 7.3BT,44 {2H, in), T.3Q-7.33 (1H, m), 7.0^7,19 (2H, m ), SJ3 (2H, s), 3J7-3.34 (2H Q, 2,^2 (s, S H>, 1.98-2J2 (4Ht m), 17^ 1.§7 (3 H, m)tf ^1*1,34 (3H, m); HPIG44S1: 1'84m[n,On 4筇1-5 Ph 03⁄4 H o ^ ^ {i〇〇MHz, DMSO^: δ S,S1^ 8.7D (1H, m}f 8.^8.44 {2H, br. s ), 7,65-7,81 (1H, br s)f 7,52-7,65 (SH, ni), ?.^7,43 pH, m)f 7,06^7,18 (1Ht m ), (2H* br s)f 3.32^3.40 <2H, m》》Z&l (3HS 砵1.58^04 (7H im), 130-160 (2Η,ϊη); HPLOMS a; 2,09 rnri, Mfz 43St 1 Ph CH2 H •^VWW o % , HN_(4l_z, CDCb}: 5 8.4& BJ6 (1H, m), 7.62-7 J5 (3H, in}, 7J4-7M (2Ht m>f 7 ,11-7.23 (2H, m)f 6.91 {1H, 4 S Luo 3 C2H, s)t 327435 Deep H, !), 2.57 (SHs S), 1JS-2.11 (4H, ii), 120-140 m) ^ 〇7S-0.95 ¢23⁄4 m); HPLC-MS t: 1,75 mh, m&435 ί-7 \o 03⁄4 H * 1H HMR (405 MHz, DySOS): δ 8, 61 (! H, d) , S37 (t H d)f 8.10.7*97 {4 K m), 7.87-7,80 (1 H, td), 7M {1 Hf bns.)t 7 JO (1 H, br,s4 7, 15 (1 Hf dd), 43⁄4 p H, $>, 3,51-327 <3 Η, Hfl), 199 (2 H, <f), 1,85 (4 H, dd), 1JS- | 162 (SH, m), 1.^1,21 <2 H( m); I UPLG^Staaamin^ZZf^HI^ -143- 200838508 1 name\ Τ CHe H ^Vl ih mm ^ tmzf mm δ ns-1J1 (m, 2 H) umm (mf 1 1.S5* f J4 (td, 2 H) 1.9^2.09 {m, 4 H) 3,30 (t 2 ^ 3 JB (3⁄4 2 H) S.23 fsf 1 H), 7.08 <t( ZH) ?ja*?.2t (mf 1 H) 73<3 (Table 1 H) 7JS Cd4 2 H) 7.73 H 7*80 Change 1Η}8·§3 Paper 1 埽; UPLC-撇0 should be discussed, 439 Chen, 1-9 \φ F Chfe H ί^ΧΗ iS 涵R, MeOH^4) δ 123.1,35 ( m, 2 H) UMi4 (m, 3 Η) tm-2m (mf 2H) 2Μ-2ΛΒ (m, 2 H) BM 4 H| 3.36 {s, 2 H) 3⁄4 2 H) 3.92 a Η) T,18 -7,23 {ibs 2 H) 7,31-7.40 (m, 1 H) 7 J2 ft 1 H) 7.80-7.92 (mt 2 H) 8.38-S.S4 (m, 2 Hj 837 Paper 1« UPLC4M: 0.62 mifu 4m mm^ 1-10 〇Ht H 1H mmim MHI, DMSQ-m): δ sjo^s,铋c<4 ih》, sj+aso paper 1H), 8,404.30 (m, 4H), 7 J2*7 J7 {ib, 3H), aso {s, 3J7 φΐΒ, 1H)t (mB 9H); HPLOMS; 133 mia 422 1-11 Λ ch2 H ^Vi Ή NMR (400 MHz, DMSO-cBj; δ S.95 Ρ , 1H), 8,67 (A Bm m \ 1H># 840-5.23 (m% 3H), 7SS-7MZ (in, 3H)f 4,03 ($, 2H)4 3.34 {hr s, 2H)f 2.07^82(10,9H>; UPLC-MS: 0.47 mlns 422 mm^ t»12 νΟ 03⁄4 H ^ mm {400 MHz, oiso^ds): δ 8.94 {d, 1H), 8,5^8. 48 (m, 2H), 8,35 (rn, 1H)a 7JS-7.8& (ιτϊ* IH), ?.79-7M (m31H)f 7J8-T.S2 (m, 1H), 7^3 (ss 1H), 4Λ2 (s, 23⁄4 3J1 (m, 2H), let rhyme 7 (four) 1J4-117 (in·boot UPLOIWS: ChS4 44GM+_" 1-13 ν9 CHi H Ή _R 000 祖_S0^: δ 8.69 -S.^ (ms 23⁄4 8.36-8.22 {mt 3H), 7,87-7,81 {m, 1H)f 7,74-7.64 ¢13⁄4 2H)f 0r 2H), 3J2 (br s, 2H)f 2,14-lSS (m# 7H)f 1,27-1,13 {m, 2H); UPL_&Chen Chen 436 earns 1-14 CHi H Qing MHz, DMSO_: δ 9M 2H)t aS4 {s, 1H3, BMQSM (tis, 1H), 8.35-8,24 (mt 2H), 7.S2 (m, 1H), 7,67 (m, 13⁄4 400 (% 2HX 3,33 (br s, 2H)a 2.08 ^1^ (m, 7H), 1J2-11S_b2H}; UPLC sprinkle 0·δ〇min* 423 Gu Ling HI, 1-1S 03⁄4 : m 1H-NMR (400 MHz, DMSOd^; § SJ1 (1H, d) , 8.31-8,58 (4Ht m), Bm (IH, d), 8.0S {1H, s)t TJ3^7,89 (2Ht m), 7.14 (1H, dd), 3.95 {2Mf s), 343 (2H, S)t 1.774.S7 <4Hf m)f 1MA72 pH, m), 1.33^147 (2H, m), 1,04 (3H, ginseng UPLC-MS; QMZ irtn, 436 2t8, noodles. - 144- 200838508
1-1 β v〇 CHa Me : 1H-_P |4圆 涵咏 δ a_ (1Η, #, 8.3S (1Η, d),a.33 (1Η, brs), B.22 (1Ht brs^), 8.1 pHf φ, 7.θ0^?,94 (2H, iii}s 7.71 (1H( brs), 7,1θ (tH, tid)f 3J8 (2H s)( 3.47 (2H, s), 175-2.01 (4Ht rn), 14^1S1 (4H, m), 1G3 pH UPLOMS: 0名3 43S Ρ+ΗΪ+, 218 調 1-17 'να 0¾ H 1H MUR (40D mtz, DMSO-c®} δ 1^133 (mB 2 H) i J3-191 (m, S 195-2,04 2 H) 2.44 S K) 3.40 (m, 2 H) 4.00 (s, 2 Η) 7βί (d, 1 Η) Τ.βΦΖ© (mt 4 H) S,2S-S.37 (m, 2 H) a.8T {cf, 1 HK UPLC撒讎_, 1*18 V〇F 0¾ H 1H NPH (400 WMe, OMSO-dB} δ 1,18-1.3? (mf 2 H) 182«L7a (in, 3 H) 18CM.92 (hi, 2 tf Ui^.0? {mt 21¾ 3 J1437 _ _ 3‘98泰2 H5 e膝 6,97 (m( 1 H) 7.51-TJO (rn# 2 H) 7.96^ B,06 im, 2 H) 8,08-8.33 (m, 2 Η) 8.60-臓_,1峨 ΗΡΙϋ捕St 2.018 mb, 440 f__ 1-1 e φ CHM^ H iH^rnm poo ym, oyso^: 5 SjQ C1H d)t δ.22»β.44 {3H, m), SJ1 (1H, d), 7J6 (1H, brs), 7,81^7.88 (1H, m)* 7J8 {1H, fars), 7JS (1H, dd}, 4.02 PH, s), 3,95-4.0? (1H, m), 1J3^07 (2ΗΦ m}« i,8D^i.a2 (2H, m), 1.53^1.7? Pi 1.15«满(2a屬,1 ja iSH, 蜞 UPLC-MS: 0,62 mfn, [Mi 218ίΜ+2ΗΙ2^ ㈣ V〇 I mt H nm C4〇o y hz, cocy : δ bmt^ BJ2 {1H, m}t (1HS m)t δ.23-8J0 (1H, rfi)t 7J4»7,B3 (1H, m), 7.68-715 (2HS m% 7Λ6-72Ζ (1H, m), 7.01-7,07 {1H, m)f 5,03-5.17 {1H, bn 40S {2H, s); S.14^22 {2H. 2.CB« 1,94 (3Ht m), 1.&4-1T9 (2Η,γπ), 1 说 _,_ HPLC描:4,39咖440峰雕 實例2 製備式(IIB)的化合物1-1 β v〇CHa Me : 1H-_P |4圆涵咏δ a_ (1Η, #, 8.3S (1Η, d), a.33 (1Η, brs), B.22 (1Ht brs^), 8.1 pHf φ, 7.θ0^?,94 (2H, iii}s 7.71 (1H( brs), 7,1θ (tH, tid)f 3J8 (2H s)( 3.47 (2H, s), 175-2.01 ( 4Ht rn), 14^1S1 (4H, m), 1G3 pH UPLOMS: 0 name 3 43S Ρ+ΗΪ+, 218 1-17 'να 03⁄4 H 1H MUR (40D mtz, DMSO-c®} δ 1^133 (mB 2 H) i J3-191 (m, S 195-2, 04 2 H) 2.44 SK) 3.40 (m, 2 )) 4.00 (s, 2 Η) 7βί (d, 1 Η) Τ.βΦΖ© ( Mt 4 H) S,2S-S.37 (m, 2 H) a.8T {cf, 1 HK UPLC 雠_, 1*18 V〇F 03⁄4 H 1H NPH (400 WMe, OMSO-dB} δ 1 ,18-1.3? (mf 2 H) 182«L7a (in, 3 H) 18CM.92 (hi, 2 tf Ui^.0? {mt 213⁄4 3 J1437 _ _ 3'98 Thai 2 H5 e knee 6,97 (m( 1 H) 7.51-TJO (rn# 2 H) 7.96^ B,06 im, 2 H) 8,08-8.33 (m, 2 Η) 8.60-臓_,1峨ΗΡΙϋ arrest St 2.018 mb, 440 F__ 1-1 e φ CHM^ H iH^rnm poo ym, oyso^: 5 SjQ C1H d)t δ.22»β.44 {3H, m), SJ1 (1H, d), 7J6 (1H, brs) , 7,81^7.88 (1H, m)* 7J8 {1H, fars), 7JS (1H, dd}, 4.02 PH, s), 3,95-4.0? (1H, m), 1J3^07 (2ΗΦ m }« i,8D^i.a2 (2H, m), 1.53^1. 7? Pi 1.15« full (2a genus, 1 ja iSH, 蜞UPLC-MS: 0,62 mfn, [Mi 218ίΜ+2ΗΙ2^ (4) V〇I mt H nm C4〇oy hz, cocy : δ bmt^ BJ2 {1H , m}t (1HS m)t δ.23-8J0 (1H, rfi)t 7J4»7,B3 (1H, m), 7.68-715 (2HS m% 7Λ6-72Ζ (1H, m), 7.01-7 ,07 {1H, m)f 5,03-5.17 {1H, bn 40S {2H, s); S.14^22 {2H. 2.CB« 1,94 (3Ht m), 1.&4- 1T9 (2Η, γπ), 1 says _, _ HPLC description: 4, 39 coffee 440 peak carving example 2 Preparation of compound of formula (IIB)
-145 - 200838508 實例2-1 (_展i ^ a \ 1 ττ 機基}甲基上^ ~~ΙΓΓ^烷-2-酮.鹽酴 ^ 基)-二二==(2其毫升)的(反式)·δ_“叫-145 - 200838508 Example 2-1 (_ exhibition i ^ a \ 1 ττ machine base} methyl on ^ ~ ~ ΙΓΓ ^ alkan-2-one. salt 酴 ^ base) - two two == (2 cc) (trans)·δ_“call
-2-m(^f^, 19 50 TJ (中間物14, 30.7毫克毛o m L4,吴耳)及3善2-氟°比唆 ^m〇7 7 - ^毛克,〇·174耄旲耳)之溶液,加入碘化亞 q ο=克,〇.145毫莫耳)、反式u_環己烧二胺_5 笔升,〇.29G晕莫耳)及鱗_(154毫克,〇.726毫莫耳),在 120 C下將混合物攪拌3小時,使用—種謂驗喂蒸發 除去1,4 一 H,所得粗製品被溶解入二氯曱烧(8毫升), 15 20 過濾,將溶液濃縮,粗製品被置於Kp_NH筒上純化,以 %己烷/EtOAc的混合物溶離,所要的化合物,(反 式)-8_({[1-(2-氟苯基)_1H』比唑_3_基]胺基}甲基氟 -3-吼啶基)-1-氧雜-3-氮雜螺[4·5]癸烷酮在約15%的 EtOAc下被溶離(40亳克)。 1H-NMR (400 MHz, CDC13): δ 8.13-8.19 (1H? m), 8·06-8·10 (1Η,m),7.83-7.89 (2Η,m),7·10-7·29 (4Η,m), 5·82 (1H,d),3·90 (2H,d)5 3·15-3·21 (2H,m),2·01-2·10 (4H, m)5 1.83-1.94 (2H? m)5 1.71-1.82 (1H? m)? 1.12*1.25 (2H? m); UPLC-MS: 0·76 分鐘,440 [M+H]、 將其溶解於一氣曱烧’加入2.1當量溶解於乙鱗中之 ΙΜΗα,製得此標題化合物(40毫克)。 -146- 200838508 實例2-2 (反式VH{『1;12·氪苯基胺某}甲基)_3_ί3_ 噠畊基)-1-氧Ur氮雜場 將(反式)冬({[1-(2-氟苯基 _ 5 基)-1-氧雜-3—氮雑螺[4·5]癸烷-2-酮(以類似於製備中間物 19之方式製備,50毫克,〇·145毫莫耳)、3'氯射(可講得 物)(33.3笔克,0·290耄莫耳)、破化亞銅⑴(27·7毫克,〇145 毫莫耳)、磷酸鉀(154毫克,0.726毫莫耳)及反式4 2•二胺 基環己烷(0.017毫升,0.145毫莫耳)混合在一起並在丨如它 10 下搖動13小時,除去溶劑,粗製品以二氯甲烷淋洗,所 得粗製品立即以Biotage SP1純化,置於ΚΡ-ΝΗ 25Μ管柱 上’以環己烧及乙酸乙酯的梯度溶離,所要的化合物,(反 式)冬({[1-〇氟苯基比唑_3_基]胺基}甲基)_3-(3_噠 畊基)小氧雜-3-氮雜螺[4.5]-癸烷-2-酮以約40%的EtOAc 15 被溶離下來,回收得一種無色油質物(50毫克)。 φ 1H-NMR (400 MHz? CDC13): δ 8.96 (1H9 dd)5 8.56 (1Η, dd),7·83-7·91 (2H,m),7·49 (1H,dd),7·10-7·24 (3H,m), 5·82 (1H,d),4·22 (2H,s),3·95 (1H,brs),3.18 (2H,brm), 2.00-2.09 (2H,m)5 ι·89 (2H,td),1·71-1·83 (1H,m), 1-18-1.31 (2H? m); 然後使之與1·〇當量,在乙醚内之10 M HC1反應, 製得此標題化合物(49毫克),為一種無色固體。 -147- 200838508 ^^Ηϋ·κ·2-氟苯基V1H-吡唑'3-基1腙某}甲基V3-(l- 王盖啥:3 •基)-1 氧雜二3 -氮雜j累「4.51癸烷-2 -酮二鹽 酸鹽 在氮氣層内、室溫下,將1-(2-氟苯基)_1Η-吡唑胺 5 (2?毫克,0.152毫莫耳)及反式3-(1-甲基_1Η•吡唑基)_2_ 侧氧-1-氧雜-3-氮雜螺[4·5]癸烷-8-甲醛(中間物23, 40.1毫 克,0· 152毫莫耳)一起混合於二氯甲垸(2毫升)内,加入四 _ 異丙氧化鈦(IV)(0.089毫升,〇·305毫莫耳),將混合物攪拌 18小時,加入氫硼化鈉(17.30毫克,〇·457毫莫耳),反應 10 混合物以乙醇(2毫升)稀釋,攪拌24小時後,加入飽和的 碳酸氫鈉水溶液(1毫升)中止反應,以二氯曱烷(4()毫升) 稀釋’有機層以飽和的碳酸氫鈉水溶液(10毫升)及鹽水(10 毫升)洗滌,再使之通過一種疏水的PTFE燒結物,濃縮, 粗製品置於經ΝΗ-修飾的砍膠(Biotage)上純化,以9/1至 15 3/7的環己烷/乙酸乙酯溶離,所要的劃分被溶離於1Λ的 環己烷/乙酸乙酯下,取得49.0毫克的目標化合物,(反 鲁 式)_8_({[1-(2_氟苯基)-1Η-吡唑-3·基]胺基}甲基)_3_(1-甲 基-111-°比峻-3-基)小氧雜-3-氮雜螺[4.5]癸烧-2-酮。 1H-NMR (400 MHz? CDC13): δ 7.88 (1H5 dd)? 7.85 (1Η, 20 t),7·29 (1H,d),7·08-7·25 (3H,m),6·65 (m5 d),5·82 (1H, d)5 3·88 (2H,s)5 3·84 (3H,s),3·17 (2H,t)5 1·96-2·〇6 (4H,m), 1.80-1.91 (2H,m),1·68-1·80 (1H,m),1·15-1·25 (2H,m); UPLC-MS: 0.75 分鐘,425 [M+H]+。-2-m(^f^, 19 50 TJ (intermediate 14, 30.7 mg hair om L4, Wu ear) and 3 good 2-fluoro ° 唆^m〇7 7 - ^毛克,〇·174耄旲a solution of the ear), adding iodized sub-q ο=g, 〇.145 millimolar), trans-u_cyclohexanaldiamine _5 pen liter, 〇.29G halo) and scale _ (154 mg, 726.726 mmol, the mixture was stirred at 120 C for 3 hours, and the crude product was dissolved in dichlorohydrazine (8 ml) using 15 ml of the test. The solution was concentrated, and the crude product was purified by placing on a Kp_NH cartridge, eluting with a mixture of % hexane / EtOAc, the desired compound, (trans)-8_({[1-(2-fluorophenyl))-1 Azole-3-yl]amino}methylfluoro-3-acridinyl)-1-oxa-3-azaspiro[4·5]nonanone is dissolved in about 15% EtOAc (40 亳) Gram). 1H-NMR (400 MHz, CDC13): δ 8.13-8.19 (1H? m), 8·06-8·10 (1Η, m), 7.83-7.89 (2Η, m), 7·10-7·29 ( 4Η,m), 5·82 (1H,d),3·90 (2H,d)5 3·15-3·21 (2H,m),2·01-2·10 (4H, m)5 1.83 -1.94 (2H? m)5 1.71-1.82 (1H? m)? 1.12*1.25 (2H? m); UPLC-MS: 0·76 minutes, 440 [M+H], dissolve it in a gas-fired ' The title compound (40 mg) was obtained after the addition of 2.1 eq. -146- 200838508 Example 2-2 (trans VH{『1;12·氪Phenylamine}methyl)_3_ί3_ 哒耕基)-1-Oxyur Ur nitrogen field will (trans) winter ({[1 -(2-Fluorophenyl-5-yl)-1-oxa-3-azinospiro[4·5]nonan-2-one (prepared in a manner similar to the preparation of intermediate 19, 50 mg, 〇· 145 millimoles), 3' chlorine shot (available) (33.3 grams, 0.290 moles), broken copper (1) (27. 7 mg, 〇145 millimoles), potassium phosphate ( 154 mg, 0.726 mmol, and trans 4 2•diaminocyclohexane (0.017 ml, 0.145 mmol) were mixed together and shaken for 10 hours under, for example, 10, the solvent was removed, and the crude product was The methyl chloride was rinsed, and the obtained crude product was immediately purified by Biotage SP1 and placed on a ΚΡ-ΝΗ 25Μ column. The mixture was dissolved in a mixture of cyclohexane and ethyl acetate. The desired compound, (trans) winter ({[1- 〇Fluorophenylpyrazole _3_yl]amino}methyl)_3-(3_哒耕基)小oxa-3-azaspiro[4.5]-nonan-2-one with about 40% EtOAc 15 was dissolved and a colorless oily substance (50 mg) was obtained. φ 1H-NMR (400 MHz? CDC13): δ 8.96 (1H9 dd)5 8.56 (1Η, Dd),7·83-7·91 (2H,m),7·49 (1H,dd),7·10-7·24 (3H,m), 5·82 (1H,d),4·22 (2H, s), 3.95 (1H, brs), 3.18 (2H, brm), 2.00-2.09 (2H, m) 5 ι·89 (2H, td), 1·71-1·83 (1H, m), 1-18-1.31 (2H?m): mp. 200838508 ^^Ηϋ·κ·2-fluorophenyl V1H-pyrazole '3-yl 1腙}methyl V3-(l-wanggao:3 •yl)-1 oxabis 3 -aza j "4.51 decane-2 -one dihydrochloride salt 1-(2-fluorophenyl)_1 -pyrazolamine 5 (2 mg, 0.152 mmol) and trans in a nitrogen atmosphere at room temperature 3-(1-methyl_1Η•pyrazolyl)_2_ oxo-1-oxa-3-azaspiro[4·5]nonane-8-formaldehyde (intermediate 23, 40.1 mg, 0·152 Mix together in dichloromethane (2 ml), add tetra-isopropoxide (IV) (0.089 ml, 〇·305 mmol), stir the mixture for 18 hours, add sodium borohydride (17.30 mg, 〇·457 mmol), reaction 10 The mixture was diluted with ethanol (2 mL) and stirred 24 The reaction was quenched with EtOAc (EtOAc (EtOAc) And passing it through a hydrophobic PTFE sinter, concentrating, and the crude product is purified on a mash-modified gelatin (Biotage) and dissolved in 9/1 to 15 3/7 of cyclohexane/ethyl acetate. The desired fraction was dissolved in 1 Λ of cyclohexane/ethyl acetate to give 49.0 mg of the desired compound, (anti-ruthen) _8_({[1-(2-fluorophenyl)-1 Η-pyrazole-3· Amino]methyl}methyl)_3_(1-methyl-111-° than tern-3-yl)sodium oxa-3-azaspiro[4.5]oxadol-2-one. 1H-NMR (400 MHz? CDC13): δ 7.88 (1H5 dd)? 7.85 (1Η, 20 t), 7·29 (1H, d), 7·08-7·25 (3H, m), 6.65 (m5 d), 5·82 (1H, d) 5 3·88 (2H, s) 5 3·84 (3H, s), 3·17 (2H, t) 5 1·96-2·〇6 ( 4H,m), 1.80-1.91 (2H,m),1·68-1·80 (1H,m),1·15-1·25 (2H,m); UPLC-MS: 0.75 minutes, 425 [M +H]+.
將其溶解於二氯曱烷並加入溶解於乙醚中之1M -148- 200838508 HCl,汽提除去溶劑,在45°c、高真空下將所得固體乾燥 過夜,製得此標題化合物(49.5毫克)。 本 實例 5This was dissolved in dichloromethane and added to 1M-148-200838508 HCl dissolved in diethyl ether. The solvent was stripped, and the obtained solid was dried overnight at 45 ° C under high vacuum to give the title compound (49.5 mg). . This example 5
10 1510 15
20 氟笨基)_1H- u 比吨-3-^j 胺某丨 y 基1^11:1-二氟甲基)_3·ρ比咬基士氧雜_3_氤星螺『4.51恭校 -2_闕二鹽g参鹽 此標題化合物係以類似於製備中間物2_3之方式製 備,將(反式)-3-(1-甲基-1H-吡唑-3-基)-2-侧氧-;[_氧雜_3_ 氮雜螺[4.5]癸烷-8-甲醛換成(反式)_2_侧氧_3_[5_(三氟甲 基)-3-吡啶基]-1-氧雜_3-氮雜螺[4·5]癸烷_8_甲醛(中間物 氟莖Α)_1Η-吡唑其1胺某}甲20 fluoro phenyl)_1H- u than ton-3-^j amine 丨 y base 1^11:1-difluoromethyl) _3·ρ ratio bite ketone oxygen _3_ 氤 螺 『 "4.51 Congratulations -2_阙二盐g参盐 This title compound was prepared in a similar manner to the preparation of intermediate 2-3, (trans)-3-(1-methyl-1H-pyrazol-3-yl)-2- Side oxygen-;[_oxa-_3_azaspiro[4.5]decane-8-formaldehyde is replaced by (trans)_2_side oxygen_3_[5_(trifluoromethyl)-3-pyridyl]-1 -oxaxo-3-azospiro[4·5]decane_8_formaldehyde (intermediate fluorine stem Α)_1Η-pyrazole 1 amine one}
35, 40.8毫克,〇·124毫莫耳),製得此標題化合物(47毫克)。 此標題化合物係以類似於製備中間物2_3之方式製 ,,將(反式)-3-〇甲基-ΐΗ_吡唑_3_基)_2_侧氧氧雜_3_ 氮錶螺[4.5]癸烷冬曱醛換成(反式)_2-侧氧冬(2_ σ比畊 基)-1-氧雜-3-氮雜螺[4·5]癸烷-8-甲醛(中間物38, 4〇·6毫 克,0.155毫莫耳),製得此標題化合物(37毫克)。 ^^1:1^1,3-笨並邊^唑_5_基)_8_((「1彳2_氟茉基)_11^ -149- 200838508 吡唑-3-基1胺基μ甲某^ 此標題化合物係賴似於製備中間物μ之 備,將3:氯噠錢成5|2,u_苯并嗟二唾⑽4毫^, 0.087耄莫耳),製得此標題化合物(32·5毫克)。 , 實例2-7The title compound (47 mg) was obtained from m. This title compound was prepared in a manner similar to the preparation of intermediate 2-3, which gave (trans)-3-indolylmethyl-indole-pyrazole-3-yl-2-yl-2-pyrene-3-a snail [4.5 ] decane winter furfural replaced by (trans)_2-side oxygen winter (2_ σ ratio cultivating)-1-oxa-3-azaspiro[4·5]decane-8-formaldehyde (intermediate 38 , 4 〇·6 mg, 0.155 mmol, obtained the title compound (37 mg). ^^1:1^1,3-1,3-且边^azole_5_基)_8_(("1彳2_Fluoryl)_11^ -149- 200838508 Pyrazol-3-yl 1 Amine ^ The title compound is obtained by the preparation of the intermediate compound, and the title compound (32) is obtained by the method of 3: chlorohydrazine into 5|2, u-benzoindole (10) 4 mM, 0.087 耄mol). · 5 mg). , Example 2-7
10 氟茉某吡 錯基癸烷-2.鹽酴 i 此標題化合物係以類似於製備中間物2_2之方式製 備,將3-氯噠喷換成5|U-苯并二今茂(1〇49微^, 〇·〇87耄莫耳),製得此標題化合物(32毫克)。 1510 fluoromethyl pyridyl decane-2. salt 酴i This title compound was prepared in a manner similar to the preparation of intermediate 2_2, and the 3-chloroindole was sprayed into 5|U-benzodiazepine (1〇) The title compound (32 mg) was obtained from mp. 15
實例2-8Example 2-8
基基>5-贵咳基Ί小氡雜_3-氤雜螺Γ4.51癸烷-2- 酮鹽酸鹽 20 此標題化合物係以類似於製備中間物2_2之方式製 備’將3-氯噠喷換成5-溴-2-(曱氧基),咬(16.47毫克, 0·087笔吴耳)’製得此標題化合物(33毫克)。 實例2-9 (反氟茉基VI丑-吡唑-3-基1胺某}甲篡 -150- <S) 200838508 氣化基-3-吡啶基)-1-氣雜-3-氮雜螺「4.51癸烷-2-酮 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成3-溴吡啶1-氧化物(15.16毫克,0.087 毫莫耳),製得此標題化合物(27.2毫克)。 5 實例2-10 (反式)-8-({『1-(2-亂笨基)-Ι/f-口比g坐-3·基1胺基}甲基 甲基-3-吡啶基VI-氧雜-3-氮雜螺『4.51癸烷-2-酮鹽酸鹽 ® 此標題化合物係以類似於製備中間物2-3之方式製 1〇 備,將(反式)-3-(1-曱基-1H-吡唑-3-基)-2-侧氧-1-氧雜-3- 氮雜螺[4.5]癸烷-8-曱醛換成(反式)-3-(2-曱基-3-吼啶 基)-2-侧氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛(中間物50, 50毫克,0.182毫莫耳),製得標題化合物,為一種無色固 體(66毫克)。 15 實例2-11 • (反式氟茉基VI仄吡唑-3-基1胺基}甲基)-3-(5-嘧啶基VI-氣雜-3-氮雜螺『4.51癸烷-2-酮二鹽酸鹽 此標題化合物係以類似於製備中間物2-3之方式製 20 備,將(反式)-3-(1-曱基-1H-吡唑-3-基)-2-側氧-1-氧雜-3- 氮雜螺[4.5]癸烷-8-曱醛換成(反式)-2-側氧-3-(5-嘧啶 基)-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛(中間物53, 20毫克, 0.077毫莫耳),製得此標題化合物,為一種無色固體(21 毫克)。 -151 - 200838508 實例2-12 (反式V8-({『1 - (2-乱采基)-l/i/"〇比口坐-3-基1月安基}甲基)-3-(5-甲基-2-吼啶基)-1-氣雜-3-氮雜螺『4.51癸烷-2-酮二鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 5 備,將3-氯噠畊換成2-溴-4-甲基吡啶(14.99毫克,0.087 毫莫耳),製得標題化合物,為一種無色固體(43毫克)。 實例2-13 ’ (反式氟茉基吡唑-3-基1胺基a甲基V3-(6- 1〇 曱基-3-吡啶基)-1-氡雜-3-氮雜螺『4.51癸烷-2-酮二鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成5-溴-2-甲基吡啶(14.99毫克,0.087 毫莫耳),製得標題化合物,為一種無色固體(40毫克)。 15 實例2-14 (反式乱笨基)-1//·口比口坐-3-基1月安基)曱基)-3-(2-• 甲基-4-吡啶基M-氡雜-3-氮雜螺[4.51癸烷-2-酮鹽酸鹽 此標題化合物係以類似於製備中間物2·2之方式製 備,將3-氯噠畊換成4-溴-2-曱基吡啶(15.1毫克,0·088毫 2〇 莫耳),製得此標題化合物(15毫克)。 實例2-15 (反式)_8·({「Μ2-氟苯基)_1私吡唑-3-基Ί胺基}甲 基)-346-(曱氣基)-3-吡啶基1-1-氣雜-3-氮雜螺「4.51癸烷-2- -152- (S ) 200838508 酮鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成5-溴-2-(甲氧基)吼啶(16.5毫克,0.088 毫莫耳),製得此標題化合物(14毫克)。 5 實例2-16 (反式氟茉基Vlif-吡唑-3-基1胺基}甲基)_3-(6-氟-3-吡啶基VI-氣雜-3-氮雜螺『4.51癸烷-2-酮鹽酸鹽 ® 此標題化合物係以類似於製備中間物2-2之方式製 1〇 備,將3-氯噠畊換成5-溴-2-氟吡啶(12.3毫克,0·070毫莫 耳),製得標題化合物,為一種無色固體(18毫克)。 實例2-17 (反式)-8-(丨Π-(2-氟茉基)-1丑-吡唑-3-基1胺基}甲基V3-咪 15 唑并『1.2-al吡啶-6-基-1-氣雜-3-氮雜螺『4.5Ί癸烷-2-酮鹽酸 直 鲁此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成6-溴咪唑并[l,2-a]吼啶(17.3毫克, 0.088毫莫耳),製得此標題化合物(21.6毫克)。 實例2-18 (反式)-3-(3-乱-6-甲基-2-』比口定基氣笨基)-比 唑-3-基Ί胺基}甲基)-1-氣雜-3-氮雜螺「4.51癸烷-2-酮鹽酸 20 200838508 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成2-溴-3-氟-6-曱基吼啶(17.3毫克, 0.088毫莫耳),製得此標題化合物(25毫克)。 5 實例2-19 ί反式V8-({「M2-氟茉基)-1私吡唑-3_基1胺基)甲基)-3_Π.3_ 噻唑-2-基Μ-氣雜-3-氮雜螺[4.51癸烷-2-酮鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 * 備,將3-氯噠畊換成2-溴-1,3-噻唑(14.4毫克,0.088毫莫 ίο 耳),製得此標題化合物(16毫克)。 實例2-20 4-『(反式氟茉基仄咄唑-3-基1胺基}甲基)-2-侧氣-1-氡雜-3-氮雜螺丨4.51癸烷-3-基1笨甲腈鹽酸鹽 15 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成4-溴苯曱腈(16.0毫克,0.088毫莫 • 耳),製得此標題化合物(20毫克)。 實例2-21 2〇 3-「(反式氟茉基吡唑-3-基1胺基}甲某V2- 侧氣-1-氣雜-3-氮雜螺『4.51癸烷基1茉甲腈鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成3-溴苯曱腈(16.0毫克,0.088毫莫 耳),製得此標題化合物(15.5毫克)。 -154- 200838508 實例2-22 3-『ί反式)·8-({『Μ2·氟茉基Vlif-吡唑-3-基1胺基}甲基V2-侧氣-1-氣雜-3-氮雜螺[4.51癸烷-3-基1笨甲腈鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 5 備,將3-氯噠畊換成2-溴-1,3-苯并噻唑(18.8毫克,0.088 毫莫耳),製得此標題化合物(17.6毫克)。 實例2-23 • (反式氟苯基)-1凡吡唑-3-基1胺基}甲基)-3-(5- ίο 氟-3-吼啶基)-1-氣雜-3-氮雜螺「4.51癸烷-2-酮二鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成3-溴-5-氟吡啶(15.33毫克,0.087毫 莫耳),製得此標題化合物(23毫克)。 15 實例2-24 (反式)-8-α「Μ2-氟笨基)-1Η-吡唑-3-基1胺基}甲基 • 甲基-1H-咪唑-5-基)-1-氣雜-3-氮雜螺『4.51癸烷-2_酮鹽酸 i 此標題化合物係以類似於製備中間物2-2之方式製 20 備,將3-氯噠畊換成5-溴-1-甲基-1H-咪唑(17.0毫克,0.088 毫莫耳),製得此標題化合物(14·3毫克)。 實例2-25 (反式氟笨基VI//-吡唑-3-某1胺基a甲基V3-咪 -155 - 200838508 唑并IX2-al吼畊-3-基-1-氧雜-3-氮雜螺「4.51癸烷-2-酮鹽酸 1 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成3-溴咪唑并[l,2-a]吼畊(20.9毫克, 5 0.088毫莫耳),製得此標題化合物(17.5毫克)。 實例2-26 (反式氟茉基Vl/f-吡唑-3-基1胺基}甲基VM1- • 曱基-6-侧氣-1,6·二氫-3-吡啶基VI-氡雜-3-氮雜螺「4.51癸 ίο *完-2-酮鹽g复鹽 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成5-溴-1-甲基-2(1H)-吼啶酮(19.9毫克, 0.088毫莫耳),製得此標題化合物(12.5毫克)。 15 實例2-27 (反式)-8-({「Μ2-氟笨基Vl/i-吡唑-3-基1胺基}甲基V3-咪 • 唑并「l,2-al吡啶-7-基-1-氧雜-3-氮雜螺『4.51癸烷-2-酮鹽酸 1 此標題化合物係以類似於製備中間物2-2之方式製 20 備,將3-氯噠畊換成7-溴咪唑并[l,2-a]吼啶(20.8毫克, 0.088毫莫耳),製得此標題化合物(16毫克)。 實例2-28 (反式)-3-(2丄3-笨并咩二唑-5-基氟笨基VI//-吡 -156- 200838508 唑-3-基1胺基}甲基VI-氣雜-3-氮雜螺『4.51癸烷-2-酮鹽酸 直 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成5-溴-2,1,3-苯并崎二唑(21.0毫克, 5 0.088毫莫耳),製得此標題化合物(13毫克)。 實例2-29 (反式氟苯基VI//·吡唑-3-基1胺基}曱基 • 曱基-5-異噻唑基)-1-氣雜-3-氮雜螺[4.51癸烷-2-酮鹽酸鹽 ίο 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成5-溴-3-曱基異噻唑(18.8毫克,0.088 毫莫耳),製得此標題化合物(17.8毫克)。 實例2-30 15 (反式V8-(m-(2-氟笨基)-1/7-吡唑-3-基1胺基}曱基)-3-(1- 曱基-1开-咪唑-2-基)-1-氧雜-3-氮雜螺『4.51癸烷-2-酮鹽酸 • 直 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成2-碘-1-曱基-1H-咪唑(22.0毫克,0.088 20 毫莫耳),製得此標題化合物(12··7毫克)。 實例2-31 (反式氟笨基VI//·吡唑-3-基1胺基}甲基 嘧啶基VI-氡雜-3-氮雜螺「4.51癸烷-2-酮鹽酸鹽 -157- 200838508 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成2-溴嘧啶(16.8毫克,0.088毫莫耳), 製得此標題化合物(5.7毫克)。 5 實例2-32 (反式)-3-(2-氟-6-甲基-3-吡啶基)·8-α「1-(2_氟笨基)_1瓦·吡 唑-3-基1胺基}甲基Μ-氣雜-3-氮雜螺『4.51癸烷-2-酮鹽酸 鹽 ^ 此標題化合物係以類似於製備中間物2-2之方式製 1〇 備,將3-氯噠畊換成3-溴·2_氟-6-曱基吡啶(20.1毫克, 0.088毫莫耳),製得此標題化合物(21.0毫克)。 實例2-33 (反式氟茉基}_1仄吡唑-3-基1胺基}甲基V3-〔2-15 曱基-5-嘧啶基VI-氣雜-3-氮雜螺『4.51癸烷-2-酮鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 籲 備,將3-氯噠畊換成5-溴-2-曱基嘧啶(18.3毫克,0.088毫 莫耳),製得此標題化合物(18·3毫克)。 2〇 實例2-34 (反式氟茉基VI丑·吡唑-3-基1胺基}甲基)-3-(2-甲基-1,3-噻唑-4-基VI-氣雜-3-氮雜螺「4.51癸烷-2-酮鹽酸 簠 此標題化合物係以類似於製備中間物2-2之方式製 •158- 200838508 備,將3-氯噠畊換成4-溴-2-曱基-1,3-噻唑(18.8毫克,0.088 毫莫耳),製得此標題化合物(21毫克)。 實例2-35 5 (反式氟苯基Vlf吡唑-3-基1胺基}甲 基)-342-(三氟甲基)-5-嘧啶基-1-氣雜-3-氮雜螺[4.51癸烷 -2-酮鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 * 備,將3-氯噠畊換成5-溴-2-(三氟曱基)嘧啶(16.48毫克, 1〇 0.073毫莫耳),製得此標題化合物(18毫克)。 實例2-36 (反式氟茉基)-1凡吡唑-3-基1胺基}甲基V3-(2_ 氟-4-吡啶基VI-氡雜-3-氮雜螺「4.51癸烷-2-酮鹽酸鹽鹽酸 15 皇 此標題化合物係以類似於製備中間物2-2之方式製 • 備,將3-氯噠畊換成4-溴-2-氟吡啶(15.42毫克,0.073毫 莫耳),製得此標題化合物(21毫克)。 2〇 實例2-37 (反式>3-仏6-二甲基-4-吡啶基)-8-({『Μ2·氟苯基吡 唑-3-基1胺基}甲基氣雜-3-氮雜螺[4.51癸烷-2-酮二鹽 酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 -159- 200838508 備,將3-氯噠啩換成4-溴-2,6-二甲基吼啶(13.51毫克, 〇·〇73毫莫耳),製得此標題化合物(19毫克)。 實例2-38 -160- 200838508 基)-1-氧雜-3-氮雜螺[4·5]癸烧-8-曱醛(以類似於製備中門 物44之方式製備,40毫克,〇·154毫莫耳),製得此標題: 合物(34毫克)。 5 實例2-41 (反式鉱苯基)-1丹_ ρ比唾-;一早‘ "I胺某}甲 基)-3-(111_畔唾_3Γ基):!-氧雜-3-氮羞屋烧_2_酮鹽西免 置 B 在室溫、氣氣層下’將溶解於乙鱗中之1M jjci(2毫 ίο 升,2.0毫莫耳)加入至溶解於乙醇(2毫升)之(反 式)-8·({[1-(2_氟苯基)-111-°比唾-3_基]胺基}甲基)冬口―(四 氫-211-吼喃-2-基)-111-吼唑_3-基]-1-氧雜_3_氮雜螺[4.5]癸 烧-2-酮(中間物69, 45晕克,0.091毫莫耳)溶液,靜置一小 時後加熱至45 C ’經1小時’減壓下濃縮,殘留物被溶解 15 於MeOH(l毫升),癥入至2克的SCX筒,以MeOH,再 以在MeOH内之2M的NH3溶液溶離,合併驗性劃分, _ 減壓下濃縮’殘留物經由Biotage純化(5%-20%Substrate>5-Gold cough base 氡3- 氤 Γ Γ Γ 4.51 癸 -2- -2- ketone hydrochloride 20 This title compound was prepared in a manner similar to the preparation of intermediate 2_2. The title compound (33 mg) was obtained from the title compound (3 mg). Example 2-9 (Anti-Fluoryl VI ugly-pyrazol-3-yl 1 amine] 篡-150- <S) 200838508 Gasification-3-pyridyl)-1-hetero-3-nitrogen Heterospira "4.51 decane-2-one. This title compound was prepared in a similar manner to the preparation of intermediate 2-2. The 3-chloroindole was converted to 3-bromopyridine 1-oxide (15.16 mg, 0.087 mmol). Ear), the title compound (27.2 mg) was obtained. 5 Example 2-10 (trans)-8-({『1-(2-乱笨基)-Ι/f-口比比-3·基1Amino}methylmethyl-3-pyridyl VI-oxa-3-azaspiro"4.51 decane-2-one hydrochloride® This title compound is similar to the preparation of intermediates 2-3 Preparation of (trans)-3-(1-indolyl-1H-pyrazol-3-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane- 8-furfural is replaced by (trans)-3-(2-indolyl-3-acridinyl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-oxime Aldehyde (Intermediate 50, 50 mg, 0.182 mmol) afforded the title compound as a colourless solid (66 mg). 15 Example 2-11 • (V. Amino}methyl)-3-(5-pyrimidinyl VI-aza-3-azaspiro"4.51 decane-2-one dihydrochloride The title compound was prepared in a manner similar to the preparation of intermediate 2-3, (trans)-3-(1-indolyl-1H-pyrazol-3-yl)-2-oxo-oxy-1-oxo Hetero-3-azaspiro[4.5]decane-8-furfural is replaced by (trans)-2-oxo-3-(5-pyrimidinyl)-1-oxa-3-azaspiro[4.5 ] decane-8-furfural (Intermediate 53, 20 mg, 0.077 mmol) to give the title compound as a colorless solid (21 mg). -151 - 200838508 Example 2-12 (trans V8- ({『1 - (2-乱采基)-l/i/"〇比口口-3-基一月安基}Methyl)-3-(5-methyl-2-acridinyl) 1-β-hetero-3-azaspiro-4.51 decane-2-one dihydrochloride The title compound was prepared in a manner similar to the preparation of intermediate 2-2. 2-Bromo-4-methylpyridine (14.99 mg, 0.087 mmol) to give the title compound as a colourless solid (43 mg). 1 Amino-methyl-methyl 3-(6- 1 decyl-3-pyridyl)-1-oxa-3-azanespiro"4.51 decane-2-one dihydrochloride The title compound is similar Prepared in the preparation of intermediate 2-2, replacing 3-chloroindole with 5-bromo-2-methyl The pyridine (14.99 mg, 0.087 mmol) gave the title compound as m. 15 Example 2-14 (trans-chaotic base) -1 / / · mouth than mouth sitting -3- base January Anji) thiol)-3-(2-• methyl-4-pyridyl M-氡Hetero-3-azaspiro[4.51 decane-2-one hydrochloride This title compound was prepared in a similar manner to the preparation of intermediate 2-2, and 3-chloroindole was converted to 4-bromo-2-indole. The title compound (15 mg) was obtained from pyridine (15.1 mg, EtOAc, EtOAc). 3-mercaptoamino}methyl)-346-(helium-based)-3-pyridyl-1-n-oxa-3-azaspiro"4.51 decane-2-152-(S) 200838508 ketone Hydrochloride This title compound was prepared in a similar manner to the preparation of intermediate 2-2. The 3-chloroindole was converted to 5-bromo-2-(methoxy) acridine (16.5 mg, 0.088 mmol). This title compound (14 mg) was obtained. 5 Example 2-16 (trans-fluoro-lamyl-Vlif-pyrazol-3-yl 1amino}methyl)_3-(6-fluoro-3-pyridyl-VI- Gas-oxa-3-azaspiro-4.51 decane-2-one hydrochloride® This title compound was prepared in a manner similar to the preparation of intermediate 2-2, and 3-chloroindole was converted to 5- Bromo-2-fluoropyridine (12.3 mg, 0.070 mmol) The title compound was obtained as a colorless solid (18 mg). Example 2-17 (trans)-8-(丨Π-(2-fluoromethyl)-1 ugly-pyrazol-3-yl 1 amine Methyl group V3-mole 15 oxo and "1.2-alpyridin-6-yl-1-aza-3-azaspiro" 4.5 decane-2-one hydrochloride straight ruthen the title compound is similar to preparation Prepared by the intermediate 2-2, 3-chloroindole was converted to 6-bromoimidazo[l,2-a] acridine (17.3 mg, 0.088 mmol) to give the title compound (21.6 mg). Example 2-18 (trans)-3-(3-disorder-6-methyl-2-" is a specific base gas)-pyrazol-3-ylindolyl}methyl)-1- gas Hetero-3-azaspiro"4.51 decane-2-one hydrochloride 20 200838508 This title compound was prepared in a similar manner to the preparation of intermediate 2-2, and 3-chloroindole was converted to 2-bromo-3-fluoro -6-Mercaptoacridine (17.3 mg, 0.088 mmol) was obtained to give the title compound (25 mg). 5 Example 2-19 ίVV--({M2-fluoromumyl)-1 Azole-3_yl 1amino)methyl)-3_Π.3_thiazol-2-ylindole-gas-3-azaspiro[4.51 decane-2-one hydrochloride This title compound is similar to the preparation Intermediate 2-2 * Prepared, 3-chloroindole was converted to 2-bromo-1,3-thiazole (14.4 mg, 0.088 mmol) to give the title compound (16 mg). Example 2-20 4-"(trans-fluoromethyloxazol-3-yl-1amino}methyl)-2-lateral gas-1-oxa-3-azaspiroline 4.51 decane-3- Base 1 benzoic acid hydrochloride 15 This title compound was prepared in a similar manner to the preparation of intermediate 2-2, and 3-chloroindole was converted to 4-bromobenzonitrile (16.0 mg, 0.088 mmol). The title compound (20 mg) was obtained. Example 2-21 2〇3-"(trans-fluoromolylpyrazol-3-yl 1 amine group} A V2- side gas-1-gas hetero-3-azaspiro"4.51癸 alkyl 1 mo The title compound was prepared in a similar manner to the preparation of the intermediate 2-2, which was obtained by 3-chloroindole hydration with 3-bromobenzonitrile (16.0 mg, 0.088 mmol) to give the title compound. (15.5 mg). -154- 200838508 Example 2-22 3-『ί反式··8-({『Μ2·Fluoryl-Vlif-pyrazol-3-yl 1-amino}methyl V2-side gas- 1-oxa-3-azaspiro [4.51 decane-3-yl 1 carbonitrile hydrochloride] This title compound was prepared in a manner similar to the preparation of intermediate 2-2. The title compound (17.6 mg) was obtained from 2-bromo-1,3-benzothiazole (18.8 mg, 0.088 mmol). Example 2-23 • (trans-fluorophenyl)-1-pyrazole -3-yl 1amino}methyl)-3-(5- ίο fluoro-3-acridinyl)-1-oxa-3-azaspiro"4.51 decane-2-one dihydrochloride The title compound was prepared in a similar manner to the preparation of Intermediate 2-2, which was obtained from 3-bromoindole, 3-bromo-5-fluoropyridine (15.33 mg, 0.087 mmol).克) 15 Example 2-24 (trans)-8-α "Μ2-Fluoro"-1Η-pyrazol-3-yl 1amino}methyl•methyl-1H-imidazole-5-yl) -1-Gaoxa-3-azaspiro"4.51 decane-2-ketone hydrochloride i This title compound was prepared in a manner similar to the preparation of intermediate 2-2, and 3-chloroindole was converted to 5- Bromo-1-methyl-1H-imidazole (17.0 mg, 0.088 mmol) was obtained from the title compound (14·3 mg). Example 2-25 (trans-fluorophenyl)//-pyrazole-3 -1 amino group a methyl V3-imi-155 - 200838508 oxazolidine IX2-al 吼-3-yl-1-oxa-3-azaspane "4.51 decane-2-one hydrochloride 1 Prepared in a manner similar to the preparation of intermediate 2-2, which was prepared by replacing 3-chloroindole with 3-bromoimidazo[l,2-a](20.9 mg, 5 0.088 mmol). The title compound (17.5 mg). Example 2-26 (trans-fluoromethyl Vl/f-pyrazol-3-yl 1 amine) methyl VM1- • mercapto-6-side gas-1,6·dihydrogen -3-pyridyl VI-oxa-3-azaspiro"4.51癸ίο * pent-2-one salt g complex salt This title compound was prepared in a similar manner to the preparation of intermediate 2-2, 3-chloro Switching to 5-bromo-1-methyl-2(1H) - acridone (19.9 mg, 0.088 mmol) to give the title compound (12.5 mg). 15 Example 2-27 (trans)-8-({"Μ2-Fluoro-based Vl/i-pyrazol-3-yl 1-amino}methyl V3-m-oxazolo-"l,2-alpyridine- 7-yl-1-oxa-3-azaspiro "4.51 decane-2-one hydrochloride 1 This title compound was prepared in a manner similar to the preparation of intermediate 2-2. The title compound (16 mg) was obtained from 7-bromoimidazo[l,2-a] acridine (20.8 mg, 0.088 mmol). Example 2-28 (trans)-3-(2丄3) - stupid and oxadiazole-5-ylfluorophenyl VI//-pyridyl-156- 200838508 oxazol-3-yl 1 amine}methyl VI-gas-3-azane sulphate 4.51 decane-2- The ketone hydrochloride was prepared in a manner similar to the preparation of the intermediate 2-2, and the 3-chloroindole was converted to 5-bromo-2,1,3-benzoxazolidine (21.0 mg, 5 0.088 m This title compound (13 mg) was obtained. Example 2-29 (trans fluorophenyl VI//·pyrazol-3-yl 1 amino} fluorenyl • fluorenyl-5-isothiazolyl) -1-Herazine-3-azaspiro[4.51 decane-2-one hydrochloride ίο This title compound was prepared in a similar manner to the preparation of intermediate 2-2, and 3-chloroindole was converted to 5- Bromo-3-indolylthiazole (18.8 mg, 0.088 mmol) This title compound (17.8 mg) was obtained. Example 2-30 15 (trans V8-(m-(2-fluorophenyl)-1/7-pyrazol-3-yl 1amino} fluorenyl)- 3-(1-Mercapto-1open-imidazol-2-yl)-1-oxa-3-azaspidine "4.51 decane-2-one hydrochloride" The title compound is similar to the preparation of intermediate 2 The title compound (12··7 mg) was obtained from the title compound (2············· Example 2-31 (trans-fluorophenyl)//pyrazol-3-yl 1amino}methylpyrimidinyl VI-oxa-3-azaspiro"4.51 decane-2-one hydrochloride- 157-200838508 This title compound was prepared in a similar manner to the preparation of intermediate 2-2, which was obtained from the 3-chloroindole, which was converted to 2-bromopyrimidine (16.8 mg, 0.088 mmol) to give the title compound (5.7 mg. 5) Example 2-32 (trans)-3-(2-fluoro-6-methyl-3-pyridyl)·8-α "1-(2_fluorophenyl)_1 va·pyrazole-3 -yl 1amino}methyl hydrazine-gas oxa-3-azaspiro"4.51 decane-2-one hydrochloride ^ This title compound was prepared in a manner similar to the preparation of intermediate 2-2. Replace 3-chloroguanidine with 3-bromo-2-fluoro 6-Mercaptopyridine (20.1 mg, 0.088 mmol) gave the title compound (21.0 mg). Example 2-33 (trans-fluoromethyl}} 仄pyrazol-3-yl 1 amine} methyl V3-[2-15 decyl-5-pyrimidinyl VI-gas-3-aza snail "4.51 Cycloalkane-2-one hydrochloride This title compound was prepared in a manner similar to the preparation of intermediate 2-2, and 3-chloroindole was converted to 5-bromo-2-mercaptopyrimidine (18.3 mg, 0.088). The title compound (18·3 mg) was obtained. 2〇Example 2-34 (trans-fluoromethyl-VI ugly-pyrazol-3-yl 1-amino}methyl)-3-(2) -Methyl-1,3-thiazol-4-yl VI-aza-3-azaspiro"4.51 decane-2-one guanidine hydrochloride This title compound is prepared in a manner similar to the preparation of intermediate 2-2. 158-200838508 Preparation of the title compound (21 mg) was obtained from 4-chloroindole, 4-bromo-2-mercapto-1,3-thiazole (18.8 mg, 0.088 mmol). 35 5 (trans fluorophenyl Vlf pyrazol-3-yl 1 amino} methyl)-342-(trifluoromethyl)-5-pyrimidin-1-aza-3-azaspiro[4.51癸Alkan-2-one hydrochloride This title compound was prepared in a similar manner to the preparation of intermediate 2-2, and 3-chloroindole was converted to 5-bromo-2-(trifluoromethyl)pyrimidine (16.48). Mg, 1〇0.073 mmol) The title compound (18 mg) was obtained. Example 2-36 (trans-fluoromethyl)-1-pyrazol-3-yl 1amino}methyl-V3-(2-fluoro-4-pyridyl-VI-oxime Hetero-3-azaspiro"4.51 decane-2-one hydrochloride hydrochloric acid 15 The title compound is prepared in a manner similar to the preparation of intermediate 2-2, and the 3-chloro hydrazine is replaced by 4- This title compound (21 mg) was obtained from bromo-2-fluoropyridine (15.42 mg, 0.073 mmol). 2 〇 Example 2-37 (trans > 3-仏6-dimethyl-4-pyridyl) )-8-({『Μ2·fluorophenylpyrazol-3-yl 1amino}methylglycon-3-azaspiro[4.51 decane-2-one dihydrochloride] The title compound is similar Prepared in the preparation of Intermediate 2-2, 159-200838508, and replaced 3-chloroindole with 4-bromo-2,6-dimethylacridine (13.51 mg, 〇·〇 73 mmol). The title compound (19 mg) was obtained. Example 2-38-160-200838508 yl)-1-oxa-3-azaspiro[4·5]pyrrol-8-furfural (similar to the preparation of the middle gate) Prepared as the product 44, 40 mg, 154·154 mmol, obtained the title: Compound (34 mg). 5 Example 2-41 (trans-phenyl)-dan _ ρ than saliva-; Early ' "I amine} methyl)-3-(111_畔唾_3Γ):!-oxa-3-nitrozyl smoldering _2_ketone salt West Free B at room temperature, gas Under the layer '1M jjci (2 mM liters, 2.0 millimoles) dissolved in the scales was added to (trans)-8·({[1-(2_fluorobenzene) dissolved in ethanol (2 ml) Base) -111-° than salivin-3-yl]amino}methyl) 冬口-(tetrahydro-211-indol-2-yl)-111-carbazole-3-yl]-1-oxa _3_Azaspiro[4.5]oxacin-2-one (intermediate 69, 45 fag, 0.091 mmol) solution, allowed to stand for one hour and then heated to 45 C '1 hour' to concentrate under reduced pressure. The residue was dissolved in MeOH (1 mL), taken into a 2 g portion of an SCX cartridge, eluted with MeOH and then 2M NH3 in MeOH. Biotage purification (5%-20%
MeOH/CH2Cl2; 12MNH管柱),製得汰式卜^⑴-仏氟苯 基)-11^比嗤-3-基]胺基}曱基)-3-(1Η-°比唾-3-基)小氧雜-3-2〇 氮雜螺[4.5]癸烧-2-酮(N1015-52-1) (33毫克),為一種無色 油質物;1H-NMR (400 MHz, CDC13): δ 1〇·ΐ〇 (1H,brs), 7.76-7.93 (2H,m),7·50 (1H,d),7·08-7·25 (3H,m),6·73 (1H,brs),5·81 (1H,d),4·15-4·29 (1H,m),3·88 (2H,s),3·15 (2H,t),1.95-2.14 (4H,m),1·67-1·94 (3H,m),1.08-1.32 (2H, -161- 200838508 m); m/z 411 [M+H]+,206 [M+2H]2+ 將其溶解於二氯曱烷(2毫升)及MeOH (0.1毫升),然 後加入溶解於乙醚中之1·0Μ HC1 (2·5當量,0·20毫升, 0.20毫莫耳),靜置30分鐘,減壓下濃縮,殘留物被分散 5 於乙醚(2毫升),濾下固體,在60°c的真空下乾燥18小時, 製得標題化合物(14毫克),為一種白色固體。 實例2-42 • (反式氟茉基V1H-吡唑-3-基1胺某}甲 1〇 基)-3-ΠΗ-吡唑-4-基)-1-氧雜-3-氮雜螺『4.51癸烷-2-酮鹽酸 鹽 此標題化合物係以類似於製備實例2-41之方式製 備,使用(反式)-8-({〇(2-氟苯基比唑-3-基]胺基}曱 基)_3-[1-(四氫-2H-吼喃-2-基比唑-4-基]-1-氧雜-3-氮 15 雜螺[4·5]癸烷-2-酮(中間物70, 45毫克,0.091毫莫耳),製 得此標題化合物(34.3毫克)。 實例2-43 (反式氟茉基V1H·吡唑_3·基1胺基}甲基V3-(2· 20 吡啶基)-1-氡雜-3-氮雜螺「4.51癸烷-2-酮鹽酸鹽 此標題化合物係以類似於製備中間物2-3之方式製 備,將(反式)-3-(1-曱基-1H-吡唑-3-基)-2-侧氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛換成(反式)-2-側氧-3-(2-吼啶 基)-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛(其可利用類似於製 -162- 200838508 備中間物26之方式製備,150毫克,0.576毫莫耳),製得此 標題化合物(153毫克,52%)。 實例2-44 5 8-氟氟茉基MH-吡唑-3-基1胺基}甲基V3-(2-吡 啶基VI-氧雜-3-氮雜螺『4.51癸烷·2-酮二鹽酸鹽 此標題化合物係以類似於製備中間物2-3之方式製 備,將(反式)-3-(1-曱基-1Η-吡唑-3-基)-2-侧氧-1-氧雜-3_ ® 氮雜螺[4·5]癸烷-8-甲醛換成8-氟-2-侧氧-3-(2-吡啶基)-1- 1〇 氧雜-3-氮雜螺[4·5]癸烷-8-曱醛(中間物75,24毫克, 0.086毫莫耳),製得此標題化合物(9毫克)。 實例2-45 8-氟氟笨基V1H-吡唑-3-基1胺基}甲基)-3-(2-吡 15 啶基VI-氣雜-3-氮雜螺「4.51癸烷-2-酮 此標題化合物係以類似於製備中間物2-3之方式製 • 備,將(反式)-3-(1·曱基-1H-吡唑-3-基)-2-侧氧_1·氧雜_3_ 氮雜螺[4.5]癸烷-8-曱醛換成8-氟-2-側氧-3-(2-吡啶基)-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛(中間物74, 55毫克,0.198 20 毫莫耳),未將游離鹼轉變成鹽酸鹽,製得此標題化合物(31 毫克)。 實例2-46 (反式氟茉基V1H-吡唑-3-基1胺基}甲 -163 - 200838508 基V3-「L2,41三唑并『l,5-al吡啶-6-基-1_氣雜-3-氮雜嫘『4.51 癸烷-2-酮二鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成6-溴[1,2,4]三唑并[l,5-a]吼啶(28.7毫 5 克,0.145毫莫耳),製得此標題化合物(42.4毫克,55%)。 實例2-47 (反式氟茉基V1H-吡唑-3-基1胺基}甲 • 基)-3_「1义41三唑并「4,3-al吡啶-6-基-1-氣雜-3-氮雜螺『4.51 ίο 癸烷-2-酮二鹽酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 備,將3-氯噠畊換成6-溴[1,2,4]三唑并[4,34]吼啶(28.7毫 克,0.145毫莫耳),製得此標題化合物(28·4毫克,36%)。 15 實例2-48 (反式)-8-({『1-(2_乱笨基)-1Η-^比。坐_3_基1胺基}甲基_ • 甲基-1H-吡唑-4-基VI-氣雜-3-氮雜螺『4.51癸烷-2-酮二鹽 酸鹽 此標題化合物係以類似於製備中間物2-2之方式製 20 備,將3-氯噠畊換成4-碘-1-甲基-1H-吡唑(30.8毫克,0.148 毫莫耳),製得標題化合物(39.7毫克,54%)。 實例2-49 (反式茉基-1^吡唑_3_基)胺基Ί甲基13-(3-吡啶 -164- 200838508 基VI-氣雜-3-氮雜螺『4.51癸烷-2-酮鹽酸鹽 此標題化合物係以類似於製備中間物2-3之方式製 備,將(反式)-3-(1-曱基-1H-吡唑-3-基)-2-侧氧-1-氧雜-3-氮雜螺[4.5]癸烷-8-曱醛換成(反式)-2-侧氧-3-(3-吼啶 5 基)-1-氧雜氮雜螺[4·5]癸烷_8-曱醛(以類似於製備中間 物44之方式製備,40毫克,0.154毫莫耳),製得標題化合 物(40毫克)。 • 實例2-50 1〇 (順式氟茉基吡唑-3-基1胺基)甲基)-3-(3- °比咬基)-1-氧雜-3 -氮雜螺『4.51癸烧-2-酮鹽酸鹽 此標題化合物以類似於實例2-3之方式製備,將(反 式)-3-(1-曱基-1Η^比唑-3-基)-2-側氧-1-氧雜-3-氮雜螺[4.5] 癸烷-8-曱醛換成(順式)-2-側氧-3-(3-吡啶基)-1-氧雜-3-氮 15 雜螺[4.5]癸烷-8-曱醛(中間物41,55毫克,0.211毫莫耳), 製得此標題化合物(56毫克)。 實例2-51 M2-氟茉基反式V2-侧氣-3-(2-吡啶基)-1-氣雜-3-氮 2α 雜螺『4.51癸-8-基1甲基卜胺基)-1好-吡唑-4-甲腈 將(反式)_8-({[1-(2-氟苯基)-4-碘-1Η-吼唑-3-基]胺基} 曱基)-3-(2-吡啶基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮(中間 物77, 56毫克,0·102毫莫耳)、碘化亞銅(Ι)(1·948充克, 10.23毫莫耳)及KCN(7.99毫克,0.123毫莫耳)共置於一圓 -165- 200838508 底燒瓶内,將氮氣充填入瓶中三遍,加入甲苯(1毫升 再加入収二甲基4乙二胺(1〇89微升,毫莫 =),再將溶液在110〇C下加熱3〇小時2〇分鐘,加入7 % 宅克的KCN、1.94毫克的Cul及10.9微升的砂,_二曱基 5 巧乙二胺’在U〇°C下加熱混合物,再18小時,加入 1 〇耄升的飽和的κζ(:〇3溶液’水溶液層以丨〇亳升的Ac〇Et 萃取三遍,合併有機層,以10亳升的鹽水洗條,經叫肌 • 乾燥,過濾,濃縮至乾,粗製品藉由快速層析法純化(ISC0 。⑽魔疆,^克石夕膠管柱)’以下述梯度溶離:a:環己 1〇 烧/B: AC〇Et: 〇% B,[4 分鐘,0%至 25% B,14.3 分鐘,25% B, 2.9分鐘,製得15.8毫克的無色壤質物,藉纟μ· 將其純化,製得此標題化合物(4·9毫克Uy)。 實例2-52 15 ϋ^-({『Η2_ 氟苯基 • 见基)-3-(2-吡啶基)-ι-氧雜二登烷_2•酮 將氟化舒(23.35毫克,0.402亳莫耳)及碘化亞銅⑴⑺ 毫克,0.402毫莫耳)置於在氮氣層内之燒瓶内,在高直空 下,以加熱槍將固體加熱直到出現帶綠色顏色,將反應混 20 合物冷卻至室溫,加入溶解於二甲基曱萨胺(〇365 毫升)之(反式氟苯基^秦出♦坐冬基]胺基} 甲基)-3-(2- η比0¾:基)-1 -氧雜_3 -氮雜螺[4.5]癸烧_2•酮(中間 物77, 200毫克,0.365毫莫耳)的溶液,加入N_甲基_2_吡 錢(0.365毫升),接著加人三氟甲基三甲基石夕烧(〇 〇54毫 -166- 200838508 升,〇.奶毫莫耳),在室溫下授拌18小時3〇分鐘,冷卻 至室溫,力口 15毫升的濃氨水稀釋,以1〇毫升的a趣 萃取四遍,合併有機層,以15毫升的鹽水洗祿,經Na2S〇4 乾燥,過滤’濃縮至乾’殘留物再經快速層析法純化(isc〇 COMPANION,12克石夕膠管柱)’以下述梯度溶離a 烧/B: AcOEt: 〇%B,2>1 分鐘,〇%B 至 25%b i3.9 分鐘, 2細,5.4分鐘’ 25%B至5〇%Β, Η分鐘,·B 3 2分 鐘,再藉㈣掌製備性HPLC純化,製得標題化合物,為 一種白色固體(3.7毫克,2%)。 列 2-53MeOH/CH2Cl2; 12MNH column), the preparation of the formula (1)-仏 fluorophenyl)-11^ than indole-3-yl]amino} fluorenyl)-3-(1Η-° than saliva-3- a small oxa-3-2〇 azaspiro[4.5] oxazol-2-one (N1015-52-1) (33 mg) as a colorless oily substance; 1H-NMR (400 MHz, CDC13): δ 1〇·ΐ〇(1H,brs), 7.76-7.93 (2H,m),7·50 (1H,d),7·08-7·25 (3H,m),6·73 (1H,brs ),5·81 (1H,d),4·15-4·29 (1H,m),3·88 (2H,s),3·15 (2H,t),1.95-2.14 (4H,m) ,1·67-1·94 (3H,m),1.08-1.32 (2H, -161- 200838508 m); m/z 411 [M+H]+,206 [M+2H]2+ dissolve it in Dichloromethane (2 ml) and MeOH (0.1 ml), then added 1·0 Μ HCl (2·5 eq., 0·20 ml, 0.20 mmol) dissolved in diethyl ether, and allowed to stand for 30 minutes. The title compound (14 mg) was obtained as a white solid. Example 2-42 • (trans-fluoromethyl-V1H-pyrazol-3-yl 1amine}}monomethyl)-3-indole-pyrazol-4-yl)-1-oxa-3-aza Spirulina 4.51 decane-2-one hydrochloride This title compound was prepared in a similar manner to the preparation of the compound 2-41 using (trans)-8-({〇(2-fluorophenylpyrazole-3-) Amino]amino}indolyl)_3-[1-(tetrahydro-2H-indol-2-ylpyrazol-4-yl]-1-oxa-3-nitro-15 heterospiro[4·5]癸Alkan-2-one (Intermediate 70, 45 mg, 0.091 mmol) was obtained to give the title compound (34.3 mg). Example 2-43 (trans-fluoro-lamyl V1H. pyrazole. }Methyl V3-(2·20 pyridinyl)-1-oxa-3-azanespiro"4.51 decane-2-one hydrochloride This title compound was prepared in a similar manner to the preparation of intermediate 2-3. , (trans)-3-(1-indolyl-1H-pyrazol-3-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-furaldehyde Replaced with (trans)-2-oxo-3-(2-acridinyl)-1-oxa-3-azaspiro[4.5]decane-8-furfural (which can be used similarly to - 162-200838508 Prepared as intermediate 26, 150 mg, 0.576 mmol, mp. 8-Fluorofluoromethyl MH-pyrazol-3-yl 1amino}methyl V3-(2-pyridyl VI-oxa-3-azaspiro"4.51 decane-2-one dihydrochloride The title compound was prepared in a manner analogous to the preparation of intermediate 2-3, (trans)-3-(1-indolyl-1 Η-pyrazol-3-yl)-2- oxo-1- oxo- 3_ ® Azaspiro[4·5]decane-8-formaldehyde is replaced by 8-fluoro-2-oxo-3-(2-pyridyl)-1- 1〇oxa-3-azaspiro[4 5) decane-8-furfural (intermediate 75, 24 mg, 0.086 mmol) to give the title compound (9 mg). Example 2-45 8-Fluorofluoro-based V1H-pyrazole-3 -yl 1amino}methyl)-3-(2-pyridylpyridinyl VI-aza-3-azaspiro) 4.51 decane-2-one The title compound is similar to the preparation of intermediate 2-3 Preparation, preparation, (trans)-3-(1·indolyl-1H-pyrazol-3-yl)-2-sideoxy_1·oxa~3_azaspiro[4.5]decane- 8-furfural was replaced by 8-fluoro-2-oxo-3-(2-pyridyl)-1-oxa-3-azaspiro[4.5]decane-8-furfural (intermediate 74, 55 The title compound (31 mg) was obtained from the title compound (yield: m. }甲-163 - 200838508 基基3-"L2,41 triazole and "l,5-alpyridine-6-yl-1_oxa-3-azaindole" 4.51 decane-2-one dihydrochloride This title compound was prepared in a similar manner to the preparation of intermediate 2-2. The 3-chloroindole was converted to 6-bromo[1,2,4]triazolo[l,5-a]acridine (28.7 m. The title compound (42.4 mg, 55%) was obtained. Example 2-47 (trans-fluoro-lamyl V1H-pyrazol-3-yl 1 -amino} methyl group)-3_"1yi 41 triazole and 4,3-alpyridine-6-yl-1-ethane Hetero-3-azaspiro"4.51 ίο decane-2-one dihydrochloride The title compound was prepared in a similar manner to the preparation of intermediate 2-2, and 3-chloroindole was converted to 6-bromo[1] , 2,4]triazolo[4,34]acridine (28.7 mg, 0.145 mmol) to give the title compound (28·4 mg, 36%). 15 Example 2-48 (trans) 8-({『1-(2_乱笨基)-1Η-^ ratio. Sit _3_基基胺}methyl_ • Methyl-1H-pyrazole-4-yl VI-gas-hetero-3 -Azaspiro"4.51 decane-2-one dihydrochloride The title compound was prepared in a manner similar to the preparation of intermediate 2-2, and 3-chloroindole was converted to 4-iodo-1- The title compound (39.7 mg, 54%) was obtained as the title compound (3. <RTI ID=0.0>#</RTI> </RTI> <RTIgt; Methyl 13-(3-pyridine-164-200838508-based VI-gas-hetero-3-azaspiro-4.51 decane-2-one hydrochloride This title compound was prepared in a similar manner to the preparation of intermediate 2-3. , (trans)-3-(1-indolyl-1H-pyrazol-3-yl)-2-oxo-1-oxo-3 -Azaspiro[4.5]decane-8-furfural is replaced by (trans)-2-oxo-3-(3-acridin-5yl)-1-oxazaspiro[4·5]癸Alkano-8-furfural (prepared analogously to the preparation of intermediate 44, 40 mg, 0.154 mmol) afforded the title compound (40 mg). Zyridin-3-yl 1amino)methyl)-3-(3- ° butyl)-1-oxa-3-azane sulphate "4.51 oxime-2-one hydrochloride This title compound is similar Prepared in the manner of Example 2-3, (trans)-3-(1-indolyl-1Η^bisazol-3-yl)-2-oxo-1-oxa-3-azaspiro[4.5 ] decane-8-furfural is replaced by (cis)-2-oxo-3-(3-pyridyl)-1-oxa-3-nitro-15 heterospiro[4.5]decane-8-furfural (Intermediate 41, 55 mg, 0.211 mmol) afforded the title compound (56 mg). m. - gas-hetero-3-nitrogen 2α snail "4.51 癸-8-yl 1 methyl amidino)-1-pyrazole-4-carbonitrile will (trans)_8-({[1-(2- Fluorophenyl)-4-iodo-1Η-oxazol-3-yl]amino} fluorenyl)-3-(2-pyridyl)-1-oxa-3-azaspiro[4.5]decane- 2-ketone (intermediate 77, 56 mg, 0 · 102 millimolar), cuprous iodide (Ι) (1·948 charged, 10.23 mmol) and KCN (7.99 mg, 0.123 mmol) were placed in a round -165-200838508 bottom flask, Nitrogen was filled into the bottle three times, toluene was added (1 ml and then dimethyl 4 ethylenediamine (1 〇 89 μl, mmol =) was added, and the solution was heated at 110 ° C for 3 〇 2 〇 min. Add 7% of KKK, 1.94 mg of Cul and 10.9 μl of sand, _dimercapto-5-diethylenediamine' to heat the mixture at U ° ° C for another 18 hours, add 1 liter of saturation The κζ(:〇3 solution' aqueous layer was extracted three times with soared Ac〇Et, the organic layer was combined, and the strip was washed with 10 liters of brine, soaked in muscles, dried, filtered, concentrated to dryness, crude product Purified by flash chromatography (ISC0). (10) Mojiang, ^克石夕胶管柱) 'Dissolve in the following gradient: a: cyclohexanil 1 / B: AC〇Et: 〇% B, [4 minutes, 0% to 25% B, 14.3 minutes, 25 The title compound (4.99 mg Uy) was obtained by purifying 15.8 mg of a smectite free material. Example 2-52 15 ϋ^-({『Η2_ fluorophenyl• seeyl)-3-(2-pyridyl)-ι-oxadipentane-2•one will be fluorinated (23.35 mg, 0.402亳) Moen) and cuprous iodide (1) (7 mg mg, 0.402 mmol) were placed in a flask in a nitrogen atmosphere. Under high direct air, the solid was heated by a heat gun until a greenish color appeared, and the reaction was mixed. Cool to room temperature and add (trans fluorophenyl) to the base of the dimethyl bissalamine (〇 365 ml) amine methyl}-3-(2- η ratio 03⁄4: a solution of -1 -oxa-3-azaspiro[4.5]pyrene-2 ketone (intermediate 77, 200 mg, 0.365 mmol), adding N_methyl_2_pyridin (0.365 ML), followed by addition of trifluoromethyltrimethyl sulphur (〇〇54-166-200838508 liters, 〇. milk millimolar), stir at room temperature for 18 hours and 3 minutes, cooled to room temperature, Dilute 15 ml of concentrated ammonia water, extract four times with 1 〇 ml, combine the organic layers, wash with 15 ml of brine, dry with Na2S〇4, filter 'concentrate to dry' residue and then pass through the rapid layer. Analytical purification (isc〇COMPANION, 12 grams of Shiqi gum Column) 'Dissolve a burn/B with the following gradient: AcOEt: 〇%B, 2> 1 minute, 〇%B to 25% b i3.9 minutes, 2 fine, 5.4 minutes ' 25%B to 5〇%Β, The title compound was obtained as a white solid (3.7 mg, 2%). Column 2-53
式 V8-((『4-氤葡竽 i、1ΤΤ πϊϊ T ..... ^基 ι 胺某" 基吡啶.基 15 20 將(反式)-2-侧氧_3_(2_吼咬基)小氧雜_3_氮雜螺[4 5 头燒-8-甲醛(以類似於製備中間物%之方式製備,加遽 克,0.113毫莫耳)及4H_(2_i苯基邮“比吐冬胺^中指 物78, 22毫克,0.113亳莫耳)溶解於u_二氯乙燒⑽德 升),然後加入異丙氧化鈦(IV)(66」微升,〇 225毫莫 在60°C下授拌混合物’經5小時3〇分鐘,冷卻至室溫, ^入甲醇(220微升’再加入氯蝴化納(12 79毫克,㈣8養 莫耳),在室溫下攪拌16小時1〇分鐘,加入2毫升的WO 之飽和的溶液,在室溫下攪拌5分鐘,過遽,漁餅經r 毫升的AcOEt洗條’將此雙相的溶液移置於分液漏斗,卷 下有機層’水洛液層以5亳升的Ae〇Et萃取,合併有機層 -167- 200838508 以5耄^的鹽水洗滌,經Na2S〇4乾燥,過濾,濃縮至乾, ^邊物藉由快速層析法純化(ISCO COMPANION,12克矽 膠官柱),以下述梯度溶離:A:環己烷/B: AcOEt: 0%B,1.8 =鐘,0%至25% B,17.9分鐘,25% Β,3·6分鐘,收集相 當於所_要化合物之劃分,減壓下除去溶劑,瓦留物被溶解 於1〇笔升的DC1V[,令此溶液通過〗克的scx筒,再以 15,升的DCM、15毫升的MeOH洗滌此筒,化合物以 W晕升的在MeOH内之2]\4]^3溶液溶離,減壓下蒸發 除去〉谷劑,製得此標題化合物,為一種黃色薄膜(20.2毫 克,40%)〇 ±M^Zz54 15 氟茉某νιπ吡碎果1胺基}甲 -3_ 氮雜嫘[4.51^2-¾ 此標題化合物以類似於實例2-2之方式製備,將(反 式)-t({[l-(2-氟苯基)_1H^比唑_3-基]胺基}甲基)_丨_氧雜 3-氮雜螺[4.5]癸烧-2-酮換成(反式)-8-({[4-氟-i_(2-氟苯 基)-1Η_π比峻I基]胺基}曱基)小氧雜冬氮雜螺[4·5]癸烷 -2-酮(中間物79, 50毫克,〇138毫莫耳),製得標題化合 物,為一種無色薄膜物(22.1毫克,34.5%)。 三氟甲某vm—吡唑_3_基~|胺基} 氡雜嫘「4.51 癸烷:2-酮 20 200838508 此標題化合物以類似於實例2-3之方式製備,將(反 式)-3-(1-曱基-1H-吼唑-3-基)-2·侧氧-1-氧雜-3-氮雜螺[4.5] 癸烷-8-曱醛換成(反式>2-侧氧-3-(3-噠畊基)-1-氧雜-3-氮 雜螺[4.5]癸烷-8-曱醛(中間物82,95毫克,0.362毫莫耳) 且將1_(2-氟苯基)-1Η-吼唑-3-胺換成1-(2-氟苯基)-5-(三氟 曱基)-111-吼嗤-3-胺(中間物84, 97.6毫克,0.398毫莫耳), 製得標題化合物,為一種白色固體(74.5毫克,42%)。 所有的分析數據被呈現於下面表2-1中,且其中R、Formula V8-((『4-氤 竽 竽i, 1ΤΤ πϊϊ T ..... ^基ι amine " pyridine. Group 15 20 will (trans)-2-side oxygen_3_(2_吼Bite base) small oxygen _3_aza snail [4 5 head -8-formaldehyde (prepared in a manner similar to the preparation of intermediates, plus gram, 0.113 mmol) and 4H_(2_i phenyl post) More than doxamamide (the middle finger 78, 22 mg, 0.113 亳 Mo) dissolved in u_dichloroethane (10) liters, then added titanium isopropoxide (IV) (66 s microliters, 〇225 mM in The mixture was stirred at 60 ° C for 5 hours and 3 minutes, cooled to room temperature, and then added to methanol (220 μl of 'Addition of chlorine butterfly (12 79 mg, (4) 8 molars), stirred at room temperature After 16 hours and 1 minute, 2 ml of a saturated solution of WO was added, and the mixture was stirred at room temperature for 5 minutes. After the crucible, the fish cake was transferred to the separatory funnel through a r ml of AcOEt strip. The organic layer of the water layer was taken up and extracted with 5 liters of Ae〇Et. The organic layer was combined with -167-200838508 and washed with 5 耄 of brine, dried over Na 2 S 〇 4, filtered and concentrated to dryness. Purified by flash chromatography (ISCO COMPANION, 12 g silicone Column), dissolved in the following gradient: A: cyclohexane / B: AcOEt: 0% B, 1.8 = clock, 0% to 25% B, 17.9 minutes, 25% Β, 3 · 6 minutes, the collection is equivalent to _ To divide the compound, remove the solvent under reduced pressure, and disintegrate the silicon residue in 1 liter of DC1V [, let the solution pass through the gram of the scx cartridge, and then wash the cartridge with 15 liters of DCM, 15 ml of MeOH. The title compound is obtained as a yellow film (20.2 mg, 40%) 〇±M, which is obtained by dissolving the sol. ^Zz54 15 fluoromethyl νιπ pyridine fruit 1 amine group}A-3_ azaindole [4.51^2-3⁄4 This title compound was prepared in a similar manner to Example 2-2, which would be (trans)-t({[ 1-(2-Fluorophenyl)_1H^biazole-3-yl]amino}methyl)_丨_oxa-3-azaspiro[4.5]pyrene-2-one replaced (trans)- 8-({[4-Fluoro-i_(2-fluorophenyl)-1Η_π ratio I基基]amino} fluorenyl) small oxahydroazaspiro[4·5]nonan-2-one (middle The title compound was obtained as a colorless material (22.1 mg, 34.5%). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> } 氡 嫘 "4.51 decane: 2-ketone 20 200838508 This title compound was prepared in a similar manner to Example 2-3, (trans)-3-(1-indolyl-1H-indazol-3-yl) -2·Side oxy-1-oxa-3-azaspiro[4.5] decane-8-furaldehyde is replaced by (trans>2- side oxy-3-(3-indolyl)-1 -oxa-3-azaspiro[4.5]decane-8-furfural (intermediate 82, 95 mg, 0.362 mmol) and 1_(2-fluorophenyl)-1Η-carbazole-3- The amine was replaced by 1-(2-fluorophenyl)-5-(trifluoromethyl)-111-indole-3-amine (Intermediate 84, 97.6 mg, 0.398 mmol). A white solid (74.5 mg, 42%). All analytical data is presented in Table 2-1 below, and where R,
Zi、A2 及 B 為:Zi, A2, and B are:
化合物 m號 R Zi A2-B 分析數據 2,1 F H h {400 DMSD-d8): δ ai2-良 時· 7.S8 (1H·认 7.77 (1H Jd), 7ΛΖ-7Α7 (1H, m)t 7.3S (1Ht ddd), 7^7 {1Η» tc〇( ?.ia-7.24 (1H, m), 5M (1H, d), 3.91 (2H, s}t 3.03 d), 18^2.05 m), (2Hr rn), 162-1J6 {3H* m), t 剔 UPiC-MS: 0.76 fnin. 44D 2r2> H (500 MHz, OUBO-dB): δ 9.0f (1Ht d), as? {lHt d)t ?M (1Ht!), 7.71-7*80 {2H, m), 7.33-7.38 (1Nf m>. 7.26 {1H. 〇· 7·1Π22 (1H. m>s 5,S7 (1H, o), 4.12 <2R s}, 3.0? <2H, d)t 2.02 (2H, d)r 1.87 (2Ht d), 1,64^174 (3H4 xn)31.20^1.30 UPLC^S: a?3 min, 423 2^3 H (4DD MHz, DMSO-c^}: 57.93 <1Hf t), 7.75 {1Hr 7,63{1Η, φ, 7.3S (1H, ddd), 7,29 (1H% tc〇t 7,19-728 (1 H> m), (1Ht d), 5.93 (1Ht ¢, 3.81 m, s), 3 JS (3Ht s)t 3.07 (2H, 194 (2Ht d)T 1 你H, dd), 1 掷(3H· td)· 1,14-1:骑 2-4 H A- F 1H-NMR MHz. DMSO-d5): 5 9.11 (1H, <f), 8.72 {1Ht d), 8.40 <1HY t), T.93 (1Ht t)( 7 J8 (I H. id), T,3S (1H, ddd), 7.29 (1H, td), 7,19-7^ {1H, m), 5,91 (1H, φ, 4m i2H, s), 3,07 (2H, c〇, 2.0D (2H, d)t 1.89 (2H, dd), 1.08 (3Hr td>, 1.14*1,40 (3Ht m) -169 - 10 2-B vQ H w^hmr {m ym, oyso-οΒ); § as? (1H, ¢, S.44 (1li dd)t ass (1Ht dd), 7.92 f!Hf ^ (1a W, T.38 {1H (ia d), 3.9i (2Ht s}, 3Λ9 (2H, d), 2,02 Pi #, 1.$?深 ft 鱗》1 JO (謝,鱗,11^ 2-6 n fH MMR (400 ^Hz, DMSi>d8}; δ 8.44 (m, 1H)t 8,12 {dd( 1H), 7.S6 (ddt 1H)t 7m ft 1H), 7JB {«, 1^» 7A^7M (m, 3咏 5 J?饵 1均,4烟(s, 2咏 3 J7 (fcr $ ΐ!% 3游紙2哗2,勝備机7H), 1J3*11S (m.aH); UPLC-MS: 0.85 mfn, 47a 2^7 v〇*° H u mn(4mm^ Dma<B)i 5 7,89 ¢, 11¾ ?J8 魄 1H}t ?,4.7·17 {m· 4H》, _棚Cm*靴讎(s,爲綱(4 3.86 (st 2H), a?9 (br s, 1H)t (df 2H)f 198-^1.58 (m, 7H), 129-115 (mt UPLO^MS: 0,81 mm% m5 vCr- H Ή um (^m MHz, DMSO-^): δ 8.B2 (s, 2H), 7JO ¢, 1H)» 7.78 (dtt IK), 7.40-7.18 (m, 3崎,S.S5 (df. 1¾ 401 s, 1H), 3,94 (% 2H), 3,01 {s( 3H), a〇5 {A 2M), ZQMm 7H), 1.32^1.00 (mt 2H>; UPLC-MS: 0.75 me. 463 2S vQ,0 H Ή t«R (40D MHz, 0CX:b); 5 8,44 ^ myt e.23 (m, aoo (d, 1^, kst- 7J7 (m, SH), 7.32-7,10 (m, 3¾ 5.81 (df 1H), 3.88 {m, 1H), 3.72 {sf 2H), 3,19 (t, 2H),2,10-1JD(mt9H5; UPLOMS: _ min 屬{?洲 1+ a-10 v9 H f, M / *H NMR (400 ^Hz, DMSO^S): δ 8.63 (α\ 1H), 8^M,3D (m, 1H), 7^9 (t, 1HJr 7JS-7J0 (m, 2H), 7.38-7.20 (m, 4H), 5.8S {4 1H>, 3.91 (s, 2¾ 3.03 (6t 2H)( 2.S7 (s, 3H)# 22% - f J0 ft m, 7Ή), 1,12 UPLC^iS; 0.6T min, 4$S p+lfl-f 2-11 H d . _R _ 祿 DMSO· δ 9綱s, 21^^94 (s, 1H), 7.89 (f, 1H), 7J7 (dl, 1H), 740-749 (m, 3H)t 6.85 (¾ 1H), 3.09 {st 2H), ZM (ύ, 2H), 2,04-1.59 (m, 7H)S 125^.10^.2¾ 眺0概〇*71 422 p 鄉 2ri2^ H 十 0N F b ΊΗ NMR pD DMSCW6}: δ &S4 (d· 1H), {s, 1H), 7.95 (d, 1H), 7^7.82 (m, 7.3?-? J2 (m, m* 7.3^7,24 <m, 1H>, 7.27 (st 1H), 0.12 (br st iH), 4.45 ($, 2H), 3.30 (s, 2H), 2.44 (st 3¾ 2*12^1.78 UPLO-MS: 0M mla 436 [mHp 200838508Compound m No. R Zi A2-B Analytical data 2,1 FH h {400 DMSD-d8): δ ai2-good time · 7.S8 (1H·recognition 7.77 (1H Jd), 7ΛΖ-7Α7 (1H, m)t 7.3S (1Ht ddd), 7^7 {1Η» tc〇( ?.ia-7.24 (1H, m), 5M (1H, d), 3.91 (2H, s}t 3.03 d), 18^2.05 m) , (2Hr rn), 162-1J6 {3H* m), t tick UPiC-MS: 0.76 fnin. 44D 2r2> H (500 MHz, OUBO-dB): δ 9.0f (1Ht d), as? {lHt d )t ?M (1Ht!), 7.71-7*80 {2H, m), 7.33-7.38 (1Nf m>. 7.26 {1H. 〇· 7·1Π22 (1H. m>s 5,S7 (1H, o ), 4.12 <2R s}, 3.0? <2H, d)t 2.02 (2H, d)r 1.87 (2Ht d), 1,64^174 (3H4 xn)31.20^1.30 UPLC^S: a?3 Min, 423 2^3 H (4DD MHz, DMSO-c^}: 57.93 <1Hf t), 7.75 {1Hr 7,63{1Η, φ, 7.3S (1H, ddd), 7,29 (1H% tc 〇t 7,19-728 (1 H> m), (1Ht d), 5.93 (1Ht ¢, 3.81 m, s), 3 JS (3Ht s)t 3.07 (2H, 194 (2Ht d)T 1 you H , dd), 1 throw (3H·td)· 1,14-1: ride 2-4 H A- F 1H-NMR MHz. DMSO-d5): 5 9.11 (1H, <f), 8.72 {1Ht d ), 8.40 <1HY t), T.93 (1Ht t)( 7 J8 (I H. id), T,3S (1H, ddd), 7.29 (1H, td), 7,19-7^ {1H , m), 5,91 (1H, φ, 4m i2H, s), 3,07 (2H, c〇, 2.0D (2H, d)t 1.89 (2H, dd), 1.08 (3Hr td>, 1.14*1,40 (3Ht m) -169 - 10 2-B vQ H w^hmr {m Ym, oyso-οΒ); § as? (1H, ¢, S.44 (1li dd)t ass (1Ht dd), 7.92 f!Hf ^ (1a W, T.38 {1H (ia d), 3.9i (2Ht s}, 3Λ9 (2H, d), 2,02 Pi #, 1.$?deep ft scale 1 JO (thanks, scales, 11^ 2-6 n fH MMR (400 ^Hz, DMSi>d8} ; δ 8.44 (m, 1H)t 8,12 {dd( 1H), 7.S6 (ddt 1H)t 7m ft 1H), 7JB {«, 1^» 7A^7M (m, 3咏5 J? bait 1 average, 4 cigarettes (s, 2咏3 J7 (fcr $ ΐ!% 3 travel paper 2哗2, Victory machine 7H), 1J3*11S (m.aH); UPLC-MS: 0.85 mfn, 47a 2^ 7 v〇*° H u mn(4mm^ Dma<B)i 5 7,89 ¢, 113⁄4 ?J8 魄1H}t ?,4.7·17 {m· 4H》, _ shed Cm* boots 雠 (s, Outline (4 3.86 (st 2H), a?9 (br s, 1H)t (df 2H)f 198-^1.58 (m, 7H), 129-115 (mt UPLO^MS: 0,81 mm% m5 vCr - H Ή um (^m MHz, DMSO-^): δ 8.B2 (s, 2H), 7JO ¢, 1H)» 7.78 (dtt IK), 7.40-7.18 (m, 3, S.S5 (df . 13⁄4 401 s, 1H), 3,94 (% 2H), 3,01 {s( 3H), a〇5 {A 2M), ZQMm 7H), 1.32^1.00 (mt 2H>; UPLC-MS: 0.75 Me. 463 2S vQ,0 H Ή t«R (40D MHz, 0CX:b); 5 8,44 ^ myt E.23 (m, aoo (d, 1^, kst- 7J7 (m, SH), 7.32-7,10 (m, 33⁄4 5.81 (df 1H), 3.88 {m, 1H), 3.72 {sf 2H), 3,19 (t, 2H), 2,10-1JD(mt9H5; UPLOMS: _ min belongs to {?1+ a-10 v9 H f, M / *H NMR (400 ^Hz, DMSO^S): δ 8.63 (α\ 1H), 8^M, 3D (m, 1H), 7^9 (t, 1HJr 7JS-7J0 (m, 2H), 7.38-7.20 (m, 4H), 5.8S {4 1H>, 3.91 (s, 23⁄4 3.03 (6t 2H)( 2.S7 (s, 3H)# 22% - f J0 ft m, 7Ή), 1,12 UPLC^iS; 0.6T min, 4$S p+lfl-f 2-11 H d . _R _ 禄 DMSO· δ 9 s, 21^^94 (s, 1H), 7.89 (f, 1H), 7J7 (dl, 1H), 740-749 (m, 3H)t 6.85 (3⁄4 1H), 3.09 {st 2H), ZM (ύ, 2H), 2,04-1.59 (m, 7H)S 125^.10^.23⁄4 眺0 Overview*71 422 p Township 2ri2^ H Ten 0N F b ΊΗ NMR pD DMSCW6}: δ & S4 (d· 1H), {s, 1H), 7.95 (d, 1H), 7^7.82 (m, 7.3?-? J2 (m, m* 7.3^7) , 24 <m, 1H>, 7.27 (st 1H), 0.12 (br st iH), 4.45 ($, 2H), 3.30 (s, 2H), 2.44 (st 33⁄4 2*12^1.78 UPLO-MS: 0M Mla 436 [mHp 200838508
2-^13 vCr H 4 «M R 卿 _!* :δ 9斜 p, 1H)t SJ9 {β, 1H), 7.88 (s, H)> 7,81 {1,1H), 7,61 (4 m, 7.3^7,19 (mf 3H), 6,18 (s, 1¾ 4,02 2H)( 3 J9 (df 2H)f 2,92 |s, aH)( 2.tT-1.i8 (in, 4H)f 1^1.75 (mf 3H),i.ei4;42C^2m HPLC-MS; 1,92 min, 436 [MrH]^ 2-14 νό H b 1 «販师 OMSOdS): δ S 汍 1H>,良 1G«€,OT (〇it 1H)· 7领·?,8S (m, 2H>, 7M (ύ% 1H)( 7.41^7.18 (rnt 5J6 (4 tH), (e* 2H), 3.05 (d, 2¾ Zm (s, 3H), 2.07-1.58 (m, δΗ), 1^4-1,08 tH); UPLC^SS: 0.63 min, 43S fM+^ 2-W H i/ b ΊΗ HUR {4(½ MHzt DMSO-C0): δ 8,29 (d, 1H), a〇3 (ddt m)t 7MB (1,1H)t T,T? (dt, 1H), 7.40-f .1? {ms 3H), BM (4t 1H), $.86 {d, 1H)( 3.90 {s, 2h% 3,M (s, 3H), 3,03 {4 2H), 2,^-158 (oif EH), 1.24-113 (m, m: UPL^MS: CX81 min, 452 卿Ήί*· Ζ-ίΒ vCrF H t 5 Ή mm (400 MH^ DMSD«^6): δ 8,38-3,34 (mt 1H}, S*31^4 (m, 1{flf 7J0» TJi (t 1H>, 7JS (1,1¾ ?J8 ft 1H>, 7^7.31 (mt lH)f 7.30-7.16 <m, 3H), 良β4 <$· 1H》,3,M 2H>, 3*02 (4 2H), i.WT (d, 2H), iM (4 2h% MZ^M (m5 3HX 1,24-1.11 (mt 2H>^ UPLC-MS: D.^ min. 440 FM^H}+ 2·17 vC〇 H Ct f W _R卿隨仅抛0. δ 9il (hr 氮 1H), 8_S§^34 (m, 2H), S,21 W, 1H), 8,〇a (d, fH), 7-S9 (!f 1H)b 7.7S (df. IN)* 7*41*7.1§ (m, 3H), SJ§ {<!, 1H), 4D0 (s, 2H)t a〇S (4 2.0T-17D {ib, 7H), 05*1.10 〇n满; UPL關S;瞻咖 4S1 iM+H】. 2-18 H λ.. o ‘Η N❺R _ _ DMSO·^: § 7名δ 札 7,7^7.^ (πι, 2H)t 7.4^7,10 (mt 4H)t BM (d, IN), 42S 3>r s, 1H), S.0T<s( 2H), 3,02 (df EH), 2.44 (s, SH), 2,07-162 (γπ,ΙΉ), 1.30-1.16 (mt2H); UPLC-MS: D.S1 miot461 zm H Λ F 5 HUR (400 〇ySO^}; δ 7,89 ft 1H), 7JS (cfc 1H), ?,48 (d, 1H)% 7,33 (d, 1H), 7,39-7.19 {mv 3H>S 5.S6 (4 AM {tf st 1H)e 4,0$ {s, 2H), 3.05 (d, 2H), 2勝1J1㈣满,1游1.1§_灣; UPLCMyiS: _ —肩 i_]夺 2-20 vCrCN H \ Ή _R (400 MHz* DMSO. δ 7·90· TJ4 (m, 5H>, 7.3S-T.13 (m, 3H), 6.84 {d, 1H), 4,17 (br 1H), 3.9? (s, 2^t 3,05 (dt 2H5, 2,02^1.58 (m, 7H), 1,10-114 K 2j-^* UPLa^S: 0.83 mh, 440 -171- 2*21 v〇 x CM Η Ο ή nm ξ^ω mut Dmo<^: a bm (1H. #, 7,97-3,00 (1H, m)t 7M (1Ht % 7.78 (1Ht % 7.5S-7.64 m), 7*36 {1Hf ddd>f 7,28 (1¾ Ιφ, 7,1^J23 (1H, m)t 5.84 <1H, d), (2Hg s}, $.04 d), (4R m), UM-74 (3H, m), UPLOMS: 0.83 rota 440 2*22 Η H nmr (400 mz, mso-my, § sjd idq» 1H>, 7,90 ^ 1>〇t ?.S1»7Ji (m, 1H)f 7^4a-X42 i〇\ 2HJf 7.40^10 {mt 4M)t 5.B? (4 W), 460 φτ s, 1H)f a〇7 {d, 2H>, 2,13-163 (m* 7H>, 1^122 {m, 2H>; UPLC4IS: a 的 mlr% 478 2-23 Η δ F SH «a (400 mzP DMSO-dB): d 8 J1 {hi $, 1H)t 8.3a (<i, 1¾ 8.02 (dt( 1H), 7JD (ts 1^〇t 7.T8 (di 1H)e 7.4^7.20 (mt 3K>, a掷紙 1H>, 5Je 後r$, 私 2H), 3,08 (4 2HX 2,05-t.ei (m, 7% 1^1-1,15 _2Η>; UFLOMS: 0 J9 min. 440 Ρ^Η]φ a-24 vb Η "d ,<40。&#fz, DMSCN^}: 5 a〇S (s· 7.89 ft 效私 7,84 执 1H5, L40US (ra, 3H), 5.8S (<!„ 1H)t 3J7 (br s, 1l^f S.8T (sf 2H), 3J6 {s, 3H), 1D3 (d, 1H), 2A^4m (m, ?H}, 1,18-1.03 (m, 2H); UPLC·; _ 論,425 p娜 2-25 Ο Η & NMR {400 mzt DMSQ<B): 5 9.16 (4 1H)t S.49 (dd( 1H), δ.01 (d, 1H〇f β»〇β (s, 1H), 7*90〔ΜΉ), 776 (cMM), 7別❹ (m, 3HX 繊紙職 φΓ st 1H), 3·鹚鉍 2H), 3,04 (d, 2外 224-1游 UPtOMS: 0.68 mill, 462 2-26 vCc° Η Ή HMR (40) mz, PMS0-4S): ^ 7.74 (nMH>, 7H1S 机 3H)t S·紹紙 1H)f 5.8S (d, 1H), 430 ^ s, 1H), SJS (s, 2Ή), 3.43 (s, 3H), 3,03 (dt 1H), 2.0M.S6 各27 Η δ. b Ή N^R {400 MHz, DM30<B); 5 8.89 (d, 1¾ ^ $, w% 8,10 (4 in), a,02 φτ sf 1H), 7,92-7.86 (in, 2H), 7.78 (df, 1H), 7,43-7,18 (mt 3H)f 5*86 <d, 1H)f 4M(% 2H), 3J3 (br % t H), 3.0? (ctf 2H), 2,0S-1.59 (mt 7H>, 1.39*1;10 (m, 2H); VPLOm; 〇m min, 461 p+H^· 2-28 Ν-〇 Η LU 〇 ΊΗ HMR (4m MHz, DySO-cB); δ 8.40 0df 11^, 8J1 (dd, 1H), 7.89 (1,1H), 7.78 (dt, IN), 7.70{dd, 1H), 7.39-7,18 {mf 31^, 5.B5 (d, m, 4m (s, 2H), 4<m φΐ s, 1HJt 3,04 (d, 2H}f 2,06»1S1 (m, 7H), (mt 2H); UPLCS: G.84 nr^ 4S3 -172- 200838508 2-29 H Ή HUH (400 MHz^ mSO^ δ 7M ft Μ, 7.7S (dtf 1H), 7.4V7,1T {m( 3H), 6.72 (¾ 11*0, 5.8$ (41H), 4,SD (br s, 1H), a掷鉍 2H),5L34 (<f, 2H), (n\ 爾,1勝1J2柄娜 U PLOMS; 0 JS min, 442 2-30 •Λ H 1H}, T*T7 (dl, 1HK 7^4 (d, 1>|, TM φτ s, 1H>S 7^-7.33 (mt 1H)S 7JG-7.1? (m* 2HK 5.86 (d, 1 啤 4 ⑽(s, 2HX 3 (s, 3H), 3.03 (d, 2,13*1JS (mt W), 122-1,0β(ΐϊΐ,2Η); UPLC·: _ _ 425 p鄉 2-31 H NMR {4m Mmt DM§0^): S 8.72 (d, 2H), 7.8S (t, 1H), TJ8 (dt? 7.40-7J8 ¢1% 41¾ §*8S {d· 1H),未德私 2H}, 4im φτ% 1H), 3 2H)( 2^3-1^ ¢11, 现1為!‘14_-靖; 0_: 0J1 _ 422 p聊 F H & f *h mm (4Q〇 mzt dmso^: b sm id41H), 7,79 ft 1H), 7.77 {dt 1H), 7.36 {dd( 1H), 7.30-7,tT (m, 3H), S.S4 (d, 1H), 4.1β 1H>t 3^6 (s, 2H), a〇2 ¢, 2H), 2.2δ (s, 3H), 2.06*1.61 (ΓΠ,ΤΗ), 1.20-1.10 (m# 2H): UPLC-MSi OJB inror4S4P^Hl^ vCr H O, b NMR {40D MHEt DMSO^i): δ 8.^3 (s, 2H)f 7.90 ft 1Η}( 7.78 (cif, 1H}S 7.40*7,ia (m, 3H>, 5.86 (d, 1H)4 4.50 φτ s, 1H)f 3.97 2H), a〇6 (% 2H), 2,60 3H), 2.04^161 (m, 7H), 1 ^1,13 (m( 2H); UFLC-MS: CI.72 min, 437 P^Hi^ 2-34 H A 1 Ή NMR (400 MHa, OUSa-dB): § T.89 ft 1H>, 7·78 (ckM HX 7.24 龢 1¾ 7.4Ch ?/i8 (m, 3H>, 5.85 {d( 1¾ 3,99 {$, 2H), (ms, 1H), -3M (d, 2H), ZM {s. 3H), 2,D^1,61 (m, 7H)f 1.2Μ.15 (m, 2H): UPLC-M8: nm min, 442 pkHJ^ vCVCFa H .¾ .. ?h1«r (4〇d yfe Dyso-^: δ sis 2¾ 7,90 φτ Bf 1H), TJB (t, 1H), 7.41-7.16 (m? 3H), 5^5 <brs, iH), 4.18 <brss 1H), 4.08 <st 2H), 3.04 (m, 2¾ 2,09-1^1 (Γϊΐ,ΤΗ), 2H): UPLC448: 0,83 mmt 491 zm V〇F H ¾ ''H NMR ^00 ϊ^ΙΗ^ DMSO^: δ BM (4 1H)J.SS ft 1H), 7JS ft 1H>J,62 汍 11¾ 7·35 (dd, 1Η>· (m, 3HK BM W, ίΗ% ZM (s$ 2H), 3,02 {d, 1H), 2.02-158 <m, 7H>, 124-1.13 (m, 2H); UPLOMS; 0,79 m!n, 440 P+HI+ C B > -173 - 2008385082-^13 vCr H 4 «MR 卿_!* : δ 9 oblique p, 1H)t SJ9 {β, 1H), 7.88 (s, H)> 7,81 {1,1H), 7,61 ( 4 m, 7.3^7,19 (mf 3H), 6,18 (s, 13⁄4 4,02 2H)( 3 J9 (df 2H)f 2,92 |s, aH)( 2.tT-1.i8 ( In, 4H)f 1^1.75 (mf 3H), i.ei4; 42C^2m HPLC-MS; 1,92 min, 436 [MrH]^ 2-14 νό H b 1 «Trader OMSODS): δ S 汍1H>, good 1G«€, OT (〇it 1H)· 7 collar·?, 8S (m, 2H>, 7M (ύ% 1H) ( 7.41^7.18 (rnt 5J6 (4 tH), (e* 2H) , 3.05 (d, 23⁄4 Zm (s, 3H), 2.07-1.58 (m, δΗ), 1^4-1, 08 tH); UPLC^SS: 0.63 min, 43S fM+^ 2-WH i/ b ΊΗ HUR {4(1⁄2 MHzt DMSO-C0): δ 8,29 (d, 1H), a〇3 (ddt m)t 7MB (1,1H)t T,T? (dt, 1H), 7.40-f .1 ? {ms 3H), BM (4t 1H), $.86 {d, 1H)( 3.90 {s, 2h% 3,M (s, 3H), 3,03 {4 2H), 2,^-158 ( Oif EH), 1.24-113 (m, m: UPL^MS: CX81 min, 452 卿Ήί*· Ζ-ίΒ vCrF H t 5 Ή mm (400 MH^ DMSD«^6): δ 8,38-3, 34 (mt 1H}, S*31^4 (m, 1{flf 7J0» TJi (t 1H>, 7JS (1,13⁄4 ?J8 ft 1H>, 7^7.31 (mt lH)f 7.30-7.16 <m , 3H), good β4 <$· 1H》, 3, M 2H>, 3*02 (4 2H), i.WT (d, 2H), iM (4 2h% MZ^M (m5 3 HX 1,24-1.11 (mt 2H>^ UPLC-MS: D.^ min. 440 FM^H}+ 2·17 vC〇H Ct f W _Rqing with only 0. δ 9il (hr nitrogen 1H), 8_S§^34 (m, 2H), S, 21 W, 1H), 8, 〇a (d, fH), 7-S9 (!f 1H)b 7.7S (df. IN)* 7*41*7.1 § (m, 3H), SJ§ {<!, 1H), 4D0 (s, 2H)ta〇S (4 2.0T-17D {ib, 7H), 05*1.10 〇n full; UPL off S; Coffee 4S1 iM+H]. 2-18 H λ.. o 'Η N❺R _ _ DMSO·^: § 7 δ Zha 7,7^7.^ (πι, 2H)t 7.4^7,10 (mt 4H )t BM (d, IN), 42S 3>rs, 1H), S.0T<s( 2H), 3,02 (df EH), 2.44 (s, SH), 2,07-162 (γπ,ΙΉ ), 1.30-1.16 (mt2H); UPLC-MS: D.S1 miot461 zm H Λ F 5 HUR (400 〇ySO^}; δ 7,89 ft 1H), 7JS (cfc 1H), ?,48 (d, 1H)% 7,33 (d, 1H), 7,39-7.19 {mv 3H>S 5.S6 (4 AM {tf st 1H)e 4,0$ {s, 2H), 3.05 (d, 2H) , 2 wins 1J1 (four) full, 1 swim 1.1§_Bay; UPLCMyiS: _ — shoulder i_] win 2-20 vCrCN H \ Ή _R (400 MHz* DMSO. δ 7·90· TJ4 (m, 5H>, 7.3ST. 13 (m, 3H), 6.84 {d, 1H), 4,17 (br 1H), 3.9? (s, 2^t 3,05 (dt 2H5, 2,02^1.58 (m, 7H), 1, 10-114 K 2j-^* UPLa^S: 0.83 mh, 440 -171- 2*21 v〇x CM Η ή ή nm ^ω mut Dmo<^: a bm (1H. #, 7,97-3,00 (1H, m)t 7M (1Ht % 7.78 (1Ht % 7.5S-7.64 m), 7*36 {1Hf ddd>f 7,28 (13⁄4 Ιφ, 7,1^J23 (1H, m)t 5.84 <1H, d), (2Hg s}, $.04 d), (4R m), UM-74 (3H, m) , UPLOMS: 0.83 rota 440 2*22 Η H nmr (400 mz, mso-my, § sjd idq» 1H>, 7,90 ^ 1>〇t ?.S1»7Ji (m, 1H)f 7^4a- X42 i〇\ 2HJf 7.40^10 {mt 4M)t 5.B? (4 W), 460 φτ s, 1H)fa〇7 {d, 2H>, 2,13-163 (m* 7H>, 1^ 122 {m, 2H>; UPLC4IS: amlr% of 478 2-23 Η δ F SH «a (400 mzP DMSO-dB): d 8 J1 {hi $, 1H)t 8.3a (<i, 13⁄4 8.02 (dt( 1H), 7JD (ts 1^〇t 7.T8 (di 1H)e 7.4^7.20 (mt 3K>, a throwing paper 1H>, 5Je after r$, private 2H), 3,08 (4 2HX 2,05-t.ei (m, 7% 1^1-1, 15 _2Η>; UFLOMS: 0 J9 min. 440 Ρ^Η]φ a-24 vb Η "d ,<40. &#fz, DMSCN^}: 5 a〇S (s· 7.89 ft effective 7,84 1H5, L40US (ra, 3H), 5.8S (<!„ 1H)t 3J7 (br s, 1l^ f S.8T (sf 2H), 3J6 {s, 3H), 1D3 (d, 1H), 2A^4m (m, ?H}, 1,18-1.03 (m, 2H); UPLC·; _ 425 pna 2-25 Ο Η & NMR {400 mzt DMSQ<B): 5 9.16 (4 1H)t S.49 (dd( 1H), δ.01 (d, 1H〇f β»〇β (s , 1H), 7*90[ΜΉ), 776 (cMM), 7别❹ (m, 3HX 繊 paper job φΓ st 1H), 3·鹚铋2H), 3,04 (d, 2 outside 224-1 tour UPtOMS: 0.68 mill, 462 2-26 vCc° Η Ή HMR (40) mz, PMS0-4S): ^ 7.74 (nMH>, 7H1S machine 3H) t S· Shao paper 1H)f 5.8S (d, 1H), 430 ^ s, 1H), SJS (s, 2Ή), 3.43 (s, 3H), 3,03 (dt 1H), 2.0M.S6 each 27 Η δ. b Ή N^R {400 MHz, DM30<B ); 8 8.89 (d, 13⁄4 ^ $, w% 8,10 (4 in), a,02 φτ sf 1H), 7,92-7.86 (in, 2H), 7.78 (df, 1H), 7,43 -7,18 (mt 3H)f 5*86 <d, 1H)f 4M(% 2H), 3J3 (br % t H), 3.0? (ctf 2H), 2,0S-1.59 (mt 7H>, 1.39*1;10 (m, 2H); VPLOm; 〇m min, 461 p+H^· 2-28 Ν-〇Η LU 〇ΊΗ HMR (4m MHz, DySO-cB); δ 8.40 0df 11^, 8J1 (dd, 1H), 7.89 (1,1H), 7.78 (dt, IN), 7.70{dd, 1H), 7.39-7,18 {mf 31^, 5.B5 (d, m, 4m (s, 2H), 4<m φΐ s, 1HJt 3,04 (d, 2H} f 2,06»1S1 (m, 7H), (mt 2H); UPLCS: G.84 nr^ 4S3 -172- 200838508 2-29 H Ή HUH (400 MHz^ mSO^ δ 7M ft Μ, 7.7S (dtf 1H), 7.4V7, 1T {m( 3H), 6.72 (3⁄4 11*0, 5.8$ (41H), 4, SD (br s, 1H), a roll 2H), 5L34 (<f, 2H) , (n\尔,1胜1J2柄娜U PLOMS; 0 JS min, 442 2-30 •Λ H 1H}, T*T7 (dl, 1HK 7^4 (d, 1>|, TM φτ s, 1H> ;S 7^-7.33 (mt 1H)S 7JG-7.1? (m* 2HK 5.86 (d, 1 beer 4 (10)(s, 2HX 3 (s, 3H), 3.03 (d, 2,13*1JS (mt W ), 122-1, 0β(ΐϊΐ, 2Η); UPLC·: _ _ 425 p Township 2-31 H NMR {4m Mmt DM§0^): S 8.72 (d, 2H), 7.8S (t, 1H) , TJ8 (dt? 7.40-7J8 ¢1% 413⁄4 §*8S {d· 1H), not German 2H}, 4im φτ% 1H), 3 2H)( 2^3-1^ ¢11, now 1 is! '14_-靖; 0_: 0J1 _ 422 p chat FH & f *h mm (4Q〇mzt dmso^: b sm id41H), 7,79 ft 1H), 7.77 {dt 1H), 7.36 {dd( 1H) , 7.30-7, tT (m, 3H), S.S4 (d, 1H), 4.1β 1H>t 3^6 (s, 2H), a〇2 ¢, 2H), 2.2δ (s, 3H) , 2.06*1.61 (ΓΠ,ΤΗ), 1.20-1.10 (m# 2H): UPLC-MSi OJB inror4S4P^Hl^ vCr HO, b NMR {40D MHEt DMSO^i): δ 8.^3 (s, 2H) f 7.90 ft 1Η}( 7.78 (cif, 1H}S 7.40*7, ia (m, 3H>, 5.86 (d, 1H)4 4.50 φτ s, 1H)f 3.97 2H), a〇6 (% 2H), 2,60 3H), 2.04^161 (m, 7H), 1 ^1,13 (m( 2H); UFLC-MS: CI.72 min, 437 P^Hi^ 2-34 HA 1 Ή NMR (400 MHa , OUSa-dB): § T.89 ft 1H>, 7·78 (ckM HX 7.24 and 13⁄4 7.4Ch ?/i8 (m, 3H>, 5.85 {d( 13⁄4 3,99 {$, 2H), (ms , 1H), -3M (d, 2H), ZM {s. 3H), 2, D^1, 61 (m, 7H)f 1.2Μ.15 (m, 2H): UPLC-M8: nm min, 442 pkHJ^ vCVCFa H .3⁄4 .. ?h1«r (4〇d yfe Dyso-^: δ sis 23⁄4 7,90 φτ Bf 1H), TJB (t, 1H), 7.41-7.16 (m? 3H), 5^ 5 <brs, iH), 4.18 <brss 1H), 4.08 <st 2H), 3.04 (m, 23⁄4 2,09-1^1 (Γϊΐ,ΤΗ), 2H): UPLC448: 0,83 mmt 491 Zm V〇FH 3⁄4 ''H NMR ^00 ϊ^ΙΗ^ DMSO^: δ BM (4 1H)J.SS ft 1H), 7JS ft 1H>J,62 汍113⁄4 7·35 (dd, 1Η>· (m , 3HK BM W, Η % ZM (s$ 2H), 3,02 {d, 1H), 2.02-158 <m, 7H>, 124-1.13 (m, 2H); UPLOMS; 0,79 m!n , 440 P+HI+ CB > -173 - 200838508
2-37 v〇^ H ^yJ .〇 lH UMR (400 mzr mm^ 5 Τ J3* T J4 (m# m, ΊΛ^ΊΛΒ {m, 3H>f 5M (br 良 1H》f 4S4 (¾ 2H), 104 (dT 2H)上玆(¾ 6H), 2.07-1,63 (m, 7¾ 124-1Λ7 {m, 2H); ’ O?U>m: OJS min, [M+H1+ 2-38 \ζΐπ H Q , —b NIViR (4CKJ MHz( 0^80^): δ 9.5? (d^ 1N), a24 (dd, 1¾ 8*〇〇 (dd, 1¾ TJ8 ft 1H), 7JS p, 1H), ?M (dddf 1¾ 7.32-T.1S (m, 2M>, ^88 (d, 1¾ 4,05 (s, 2H), 3.0S (d, 2.06-1 ,S9 <mt Ti^, 1^1.13(01,2»); O臓議福M23 _卿 2-39 H % mm mz, 5 jsb a 1H5, 7.78 Cdt, 1H), 7.3f-7*17 (m, 3H)t 5J5 (d, 1H), 4M fs, 2H), 3.§8 (br et 1H)¥ 3.0S (d, 2h|, 2.64 (s, 2H)t (mt 7H)» 13W.i?(m,3H); UPLOMS: a7§ min, 443 [M+HJ. 2*40 v〇 H ?H NMR %mzt DMSOHj®): δ 9,04 (1H, c〇, 8,53-8.63 (2H, m), 7.^4 (1Η» dd), X9f {1H, t}$ 7JB (IH.td), 7«3S(1Ht ddc^ 72B (1H, Id), 7ΛΒ-7Μ (1H m}, 6.ES C1H,黾 404 pi s>, 3* ⑽ <2H、1名3· Z05 ¢4¾ m), 1J2-177 f3H, m)f 1,13« 1,27 (2H,_ UPLC44S: CL 掷 min, 422 p 夺 H】.and E 211 lM+2_+ 2-m vd H ύ 1H-NMR {4m fvlH^, OMSO-^): 5 7,¾ {1H, t}f 7.78 (1H, tci), 7M (1H* d), ?,3T (1H, d£!d), 7,25*7.32 (1H, m), 7.16^25 (1H, in), 6.44 (1H, φ, 5.S7 {1Η» d)f 3.84 (2H, s)f 3W (2H, d), (4H, in), 1^174{3H, m)t f J3-1.2S (2H, HFLOMS: 2 J4mln,4t1 p^HJ^ 242 v4 H hi b丨 1 Hmm ¢400 MHz, DMBO-m): δ 7M (ia 0,7 JS (2H, Id), (2Hf s), 7,3δ (1K 蝴,7»卿H爲7,17·725(1ϋ m% 5M {ίΗ, d)f 3.7i a), (2Hr d)^M-2m (4H, m)# 1.59-1.73 (3H m), 1.10^124 HPLC^S: 2,32 4112 ⑽ 脚侧2+ .:: 2-4% vO H δ tt in mm um.3 ufMo-m) b na^ 1.2β (m, 2 K) 1.^170 {m, 3 H) 178- i,aa (mff 2 1,91-us 2 h> 3.03» 3Λ7 (d, 2 H> 3.^*4 JO (m, 2 h〇 5,B7-5.9D (d, 1 H) 7.CS-T.14 (m, f H) 7,18 -T.23 (ms t H) 7.22-7,28 (eft 1 1# 7.37 (mf 1 H) 7J1*7.78 (of, 1 H) 7JS-7.B4 <d!t 1 H) 7JT-7.91 (m, 1 H} 9M4SM (m, 1 H) BMSMim, t H); UPLC-yS: aS4irun, 4ZZ fM^ c S ) -174- 2008385082-37 v〇^ H ^yJ .〇lH UMR (400 mzr mm^ 5 Τ J3* T J4 (m# m, ΊΛ^ΊΛΒ {m, 3H>f 5M (br 良1H)f 4S4 (3⁄4 2H) , 104 (dT 2H) on (3⁄4 6H), 2.07-1, 63 (m, 73⁄4 124-1Λ7 {m, 2H); ' O?U>m: OJS min, [M+H1+ 2-38 \ζΐπ HQ , —b NIViR (4CKJ MHz( 0^80^): δ 9.5? (d^ 1N), a24 (dd, 13⁄4 8*〇〇(dd, 13⁄4 TJ8 ft 1H), 7JS p, 1H), ?M (dddf 13⁄4 7.32-T.1S (m, 2M>, ^88 (d, 13⁄4 4,05 (s, 2H), 3.0S (d, 2.06-1, S9 <mt Ti^, 1^1.13 (01 ,2»); O臓议福M23 _卿2-39 H % mm mz, 5 jsb a 1H5, 7.78 Cdt, 1H), 7.3f-7*17 (m, 3H)t 5J5 (d, 1H), 4M fs, 2H), 3.§8 (br et 1H)¥ 3.0S (d, 2h|, 2.64 (s, 2H)t (mt 7H)» 13W.i?(m,3H); UPLOMS: a7§ Min, 443 [M+HJ. 2*40 v〇H ?H NMR %mzt DMSOHj®): δ 9,04 (1H, c〇, 8,53-8.63 (2H, m), 7.^4 (1Η » dd), X9f {1H, t}$ 7JB (IH.td), 7«3S(1Ht ddc^ 72B (1H, Id), 7ΛΒ-7Μ (1H m}, 6.ES C1H, 黾404 pi s> , 3* (10) < 2H, 1 3· Z05 ¢ 43⁄4 m), 1J2-177 f3H, m)f 1,13« 1,27 (2H, _ UPLC44S: CL throw min, 422 p win H].and E 211 lM+2_+ 2-m vd H ύ 1H-NMR {4m fvlH^, OMSO-^): 5 7,3⁄4 {1H, t}f 7.78 (1H, tci), 7M (1H* d), ?, 3T (1H, d£!d), 7,25*7.32 ( 1H, m), 7.16^25 (1H, in), 6.44 (1H, φ, 5.S7 {1Η» d)f 3.84 (2H, s)f 3W (2H, d), (4H, in), 1 ^174{3H, m)tf J3-1.2S (2H, HFLOMS: 2 J4mln, 4t1 p^HJ^ 242 v4 H hi b丨1 Hmm ¢400 MHz, DMBO-m): δ 7M (ia 0,7 JS (2H, Id), (2Hf s), 7,3δ (1K butterfly, 7»qing H is 7,17·725 (1ϋ m% 5M {ίΗ, d)f 3.7ia), (2Hr d)^M- 2m (4H, m)# 1.59-1.73 (3H m), 1.10^124 HPLC^S: 2,32 4112 (10) Foot side 2+ .:: 2-4% vO H δ tt in mm um.3 ufMo-m b na^ 1.2β (m, 2 K) 1.^170 {m, 3 H) 178- i, aa (mff 2 1,91-us 2 h> 3.03» 3Λ7 (d, 2 H> 3.^ *4 JO (m, 2 h〇5, B7-5.9D (d, 1 H) 7.CS-T.14 (m, f H) 7,18 -T.23 (ms t H) 7.22-7, 28 (eft 1 1# 7.37 (mf 1 H) 7J1*7.78 (of, 1 H) 7JS-7.B4 <d!t 1 H) 7JT-7.91 (m, 1 H} 9M4SM (m, 1 H) BMSMim, t H); UPLC-yS: aS4irun, 4ZZ fM^ c S ) -174- 200838508
各44 F Qr d 1H N^R (m〇Mm CDCh):52M (dt 8 R) 350 (df, 2 m 4.0(M,D3 (m, 2 Η) 4Λ2 {fersf 1H) ^84 {d( 1 Η) ?.03^ΤΛ6 (m, 1 H) 7.11^25 {01,3 M) (mt t H) 7J4-7.91 (in, 2 H) SJ!4 (4 i 1¾ 8.33 {4 1 HI; UFLC4JS: 0,9701¾. 44Dp^ 2*45 V〇 f A in nmr tmm mzf § 1.72- (mt 7 m 2*61*2.64 (m, 13.42 (¾ 2 H) 3.85 (br. s*. 1 Η) 4M (s, 2 H) §.9t (df 1 H) 7.14 {dd, 1 H) 7,17^7*23 (mt 1 H} 7,26 (i, 1 Η) 7M (ύύ, 1 H) ? J5-T.S6 (mt 2rm (tf 1 H) C41 H) 8.3S (d, t H). 2*46 vvnV H 1石 % 1H HMR <4€© MHz, DySO-dB): 6 9,10 (1 Ht dd), 8,51 (1 H, $}, a21 (1 η d^, 7M 《1 H, 738 (1 H·你 7J1”7.驗 <1 H m), 7*82-7.76 (1 H% td), 7.41^34 (1 Hf ddd), TJ2-7.2S (1Ht ld>t 7,25-7,18 {1 H, m% BM (1 Ht φ, 4.D2 (1 H, s)¥ 3.06 (2 H, ¢, 2,02 (2 Η φ 1.92 H ¢¢, 177-1.61 (3 H( (2^01¾ UPL⑽S: _ min_ 4i2 fM+Hl. 2r^T v〇^ H % 1H 涵(40涵电 _SCM均:δ _ (1 H s), (1 ft m), 8J3 W.89 0 H, m>, 7J8 (1 H, tc〇, 7M^7M (t H, ddd), 7.29 {1 H, fd)f 7^5-7.19 (1 Ht ni), 5.^ (1 H, 4,3wS8 (1 Hf $), 3.CB (2 H d), ZM (2 H, d), 1¾ (2 Hf d), 1JS-i.S4 {3 H, m)t 1*28-1.13 UPLCi-MSi 0*84 vCi H S· F 1H NMR (400141¾ DySD;^: δ 7.^ 7.βδ (1 H, m)9 7M {1 Η φ, 7.81^75 (1 Hf οι), 7.51-Z^ (1 H, m)a ?#4i-T.34 <1 H, iti)f 7^7,18 (I H, m), 5J6 (1 H, d), 3.B2 (3 H, s), 3.74 (2 Hf s), 3.04 {2 Hf d), 1,97-1,83 (4 H, m), 1.72-t.62 (3 H, m)s 123-1,£®{2H,m); UPLC44S: aS4 ml«. 425 2-49 vO H 5r oH Ή NMR (400 MHe, DMSO δ β^8 ^ 1H), 8,44 (dd, tH), 8.23 {m, 1H), Τ,β3 {m, 2H), 7JS (mt 1H), 7βδ5«7.4Β (mt 2H>t 6,24 (s, 1HJ, 4.00 (s, 2H), S.D9 (mf 2H)f 2.04-1.63 (m, TH), 1.24 (m, 2H); UPLOMS: 0.S7 min, 404 p+HI夂 2-Βύ v〇 H V 5 i UMR (4m mBO d^: δ B.9? (d, 1H)( 8,56^8.51 (m, 1H)» a,41*a34 (ht, 1H), 7J0 ft (m, 2H}, T.1S (m, 3H), &8T (d, 1H)f 4.30 |^r s, iH), 3JO (s, 2H), Zm (d, 2H), 2JC^2.00 (m, 2H), 1.83-1.60 (m, 5H)t 1.34-121 (m, 2H); UPLOMS: 0.68 422 mm^ -175- 200838508 2-51 V〇 H B ! m-mn {Am ivtte, cdgw: a b'zssm (m 1 H). 8^7-6.31 (mt f H)t 8,19 (¾ 1 Hjt (m% t H), 7 J3 {dmt ?,14, 2,02 Hz, 1 H)t 7.20-7.33 (ro, 3 H)t 7.00-?.03 {m, 1 H)s 4M ft 1 HJ* 4M (s, 2 H)t 3.32 (t, 2 H), 19^2.09 (mf 4 174* 1,S5 {m, 3 H), f ,19-1,33 {in, 2HPLC-PS: 2,38 mn, 44Z2 2-S2 V〇 H F « iH^HUR {400 COCI^; δ 1.18^1.38 (m, 2 1.76-1,05 (m, 3 19^2*09 (m, 4 H)r 3*25^33 (m, 2 H)% 4J1 (tf 1 H), 4,08 (s, 2 H}t 7.08 {ddd. 1 H% 7.19-7.31 (ms 3 H), 7 J3 (dddr 1 H), 7.87^93 (mp 1 H}, 8,09-8.11 (ms 1 N), BM (<ft 1 H), 8.34-8.3? (m, 1 H); WLC4IS:乏舫 _♦, 2-63 H Η 1H^MR (400 CDCK^: 6 835 {cil, t H), B.2§ (d, 1 7.T9-T JO {m, 2 H), 7,T3 (ddd, 1 H)a TJO-T^a Cm, 3 M}t 7.01-7.03 {mT t 3.73 (br% 1 Η), 4M (s, 2 H), 3.28 (d, 2 H)f 1.98-241 (mf 4 H)f 1.72-t,95 (mt 3 H)? 1.19^1.35 (ms 2 IFUC挪:讓 miru 祖57,2聊, 440.蝴. zm V〇 H \ #H.NMR (40D ΜΗζ, CDCI^: δ (ddt 1 H), 8.57 (ddf 1 H), 7 J7-7*90 (m, 2 H), 7.60 (dd, i H), 7.07^,26 {m, 3 H), 4J3 2 H), 3.75 ^ 1 Η), 3^δ ft 2 H), ZCKK 2 J2 {m, 4 H), 1.75^1J7 (mf 3 H), 1.18» 1.34 (mt 2 H); Rf ^ 0.2 {AcOE! 5/^dohexane 5}; UPLO^IS: 0J6 min, 441 „01 2«55 V〇 ;H }{j 1H NMR MHz, CD0I3) δ 1.12-1.25 (m, 2 H), i,m-W2 (m, 1 H), 133^2.03 (m, β Η)* 3Λ7 (% 2 H,} 3J6 0:, 1 H)s 4.20 (s, 2 (¾ a?8 (s, 1 Η), ?28-7·38 (irV2 HX 祕 7,59 ㈣ 3 _· 8 JT (佩1 H J S J7 卿H>; 帆 OMS: G*74 偷,4S1 _+H| +44 F Qr d 1H N^R (m〇Mm CDCh): 52M (dt 8 R) 350 (df, 2 m 4.0(M,D3 (m, 2 Η) 4Λ2 {fersf 1H) ^84 {d( 1 Η) ?.03^ΤΛ6 (m, 1 H) 7.11^25 {01,3 M) (mt t H) 7J4-7.91 (in, 2 H) SJ!4 (4 i 13⁄4 8.33 {4 1 HI; UFLC4JS : 0,97013⁄4. 44Dp^ 2*45 V〇f A in nmr tmm mzf § 1.72- (mt 7 m 2*61*2.64 (m, 13.42 (3⁄4 2 H) 3.85 (br. s*. 1 Η) 4M (s, 2 H) §.9t (df 1 H) 7.14 {dd, 1 H) 7,17^7*23 (mt 1 H} 7,26 (i, 1 Η) 7M (ύύ, 1 H) ? J5-T.S6 (mt 2rm (tf 1 H) C41 H) 8.3S (d, t H). 2*46 vvnV H 1 stone % 1H HMR <4€© MHz, DySO-dB): 6 9, 10 (1 Ht dd), 8,51 (1 H, $}, a21 (1 η d^, 7M "1 H, 738 (1 H· you 7J1" 7. Test <1 H m), 7*82 -7.76 (1 H% td), 7.41^34 (1 Hf ddd), TJ2-7.2S (1Ht ld>t 7,25-7,18 {1 H, m% BM (1 Ht φ, 4.D2 ( 1 H, s)¥ 3.06 (2 H, ¢, 2,02 (2 Η φ 1.92 H ¢¢, 177-1.61 (3 H( (2^013⁄4 UPL(10)S: _ min_ 4i2 fM+Hl. 2r^T v〇 ^ H % 1H 涵 (40 涵 _SCM are: δ _ (1 H s), (1 ft m), 8J3 W.89 0 H, m>, 7J8 (1 H, tc〇, 7M^7M (t H, ddd), 7.29 {1 H, fd)f 7^5-7.19 (1 Ht ni), 5.^ (1 H, 4,3wS8 (1 Hf $), 3.CB (2 H d), ZM (2 H, d), 13⁄4 (2 Hf d), 1JS-i.S4 {3 H, m)t 1*28-1.13 UPLCi-MSi 0*84 vCi HS· F 1H NMR (4001413⁄4 DySD; ^: δ 7.^ 7.βδ (1 H, m)9 7M {1 Η φ, 7.81^75 (1 Hf οι), 7.51-Z^ (1 H, m)a ? #4i-T.34 <1 H, iti)f 7^7,18 (IH, m), 5J6 (1 H, d), 3.B2 (3 H, s), 3.74 (2 Hf s), 3.04 {2 Hf d), 1,97-1,83 (4 H, m), 1.72-t.62 (3 H, m)s 123-1, £®{2H,m); UPLC44S: aS4 ml« 425 2-49 vO H 5r oH NMR NMR (400 MHe, DMSO δ β^8 ^ 1H), 8,44 (dd, tH), 8.23 {m, 1H), Τ, β3 {m, 2H), 7JS (mt 1H), 7βδ5«7.4Β (mt 2H>t 6,24 (s, 1HJ, 4.00 (s, 2H), S.D9 (mf 2H)f 2.04-1.63 (m, TH), 1.24 (m, 2H); UPLOMS: 0.S7 min, 404 p+HI夂2-Βύ v〇HV 5 i UMR (4m mBO d^: δ B.9? (d, 1H)( 8,56^8.51 (m, 1H) )» a,41*a34 (ht, 1H), 7J0 ft (m, 2H}, T.1S (m, 3H), &8T (d, 1H)f 4.30 |^rs, iH), 3JO (s , 2H), Zm (d, 2H), 2JC^2.00 (m, 2H), 1.83-1.60 (m, 5H)t 1.34-121 (m, 2H); UPLOMS: 0.68 422 mm^ -175- 200838508 2- 51 V〇HB ! m-mn {Am ivtte, cdgw: a b'zssm (m 1 H). 8^7-6.31 (mt f H)t 8,19 (3⁄4 1 Hjt (m % t H), 7 J3 {dmt ?,14, 2,02 Hz, 1 H)t 7.20-7.33 (ro, 3 H)t 7.00-?.03 {m, 1 H)s 4M ft 1 HJ* 4M (s, 2 H)t 3.32 (t, 2 H), 19^2.09 (mf 4 174* 1,S5 {m, 3 H), f ,19-1,33 {in, 2HPLC-PS: 2,38 Mn, 44Z2 2-S2 V〇HF « iH^HUR {400 COCI^; δ 1.18^1.38 (m, 2 1.76-1,05 (m, 3 19^2*09 (m, 4 H)r 3*25 ^33 (m, 2 H)% 4J1 (tf 1 H), 4,08 (s, 2 H}t 7.08 {ddd. 1 H% 7.19-7.31 (ms 3 H), 7 J3 (dddr 1 H), 7.87^93 (mp 1 H}, 8,09-8.11 (ms 1 N), BM (<ft 1 H), 8.34-8.3? (m, 1 H); WLC4IS: Lack of _♦, 2-63 H Η 1H^MR (400 CDCK^: 6 835 {cil, t H), B.2§ (d, 1 7.T9-T JO {m, 2 H), 7,T3 (ddd, 1 H)a TJO-T^a Cm, 3 M}t 7.01-7.03 {mT t 3.73 (br% 1 Η), 4M (s, 2 H), 3.28 (d, 2 H)f 1.98-241 (mf 4 H)f 1.72-t, 95 (mt 3 H)? 1.19^1.35 (ms 2 IFUC: let miru ancestor 57, 2 chat, 440. butterfly. zm V〇H \ #H.NMR (40D ΜΗζ, CDCI^: δ ( Ddt 1 H), 8.57 (ddf 1 H), 7 J7-7*90 (m, 2 H), 7.60 (dd, i H), 7.07^,26 {m, 3 H), 4J3 2 H), 3.75 ^ 1 Η), 3^δ ft 2 H), ZCKK 2 J2 {m, 4 H), 1.75^1J7 (mf 3 H), 1.18» 1.34 (mt 2 H); Rf ^ 0.2 {AcOE! 5/^ d Ohexane 5}; UPLO^IS: 0J6 min, 441 „01 2«55 V〇;H }{j 1H NMR MHz, CD0I3) δ 1.12-1.25 (m, 2 H), i,m-W2 (m, 1 H), 133^2.03 (m, β Η)* 3Λ7 (% 2 H,} 3J6 0:, 1 H)s 4.20 (s, 2 (3⁄4 a?8 (s, 1 Η), ?28-7· 38 (irV2 HX Secret 7,59 (4) 3 _· 8 JT (佩 1 HJS J7 卿 H>; Sail OMS: G*74 steal, 4S1 _+H| +
實例3 製備式(nc)的化合物Example 3 Preparation of a compound of formula (nc)
-176- 200838508 實例3吐 (反式 基)-1-氳雜 J ^ 基)胺基 1 甲農 烷_2_酮鹽酸驂 0.261毫莫耳;、可根據製備中間4勿26的方式製備,68毫克, 、田^3~苯基-5-異口号唑胺(54.4毫克,0.340亳莫 15 20 氣層、室—、Γ下丙乳化氯鈦(〇.168毫升,0·705亳莫耳),在氮 二,’里,—起混合於二氯甲烷(0.75毫升)内,經14 寸 加入二乙酸基氫硼化鈉(277毫克,1.306毫莫耳) 日士乙、=G75 $升,^310毫莫耳),將混合物鮮14小 / ’/匕&物以二氯?^*(2()毫升)稀釋’加人飽和的碳酸氣 1液(7毫升)’ 30分鐘,過濾,濾液經飽和的碳 酉夂虱納水溶液(8亳升)及鹽水(8毫升)洗滌,有機層通過疏 水的PTFE婉結物過濾’濃縮,粗製品藉切膠管柱層析 純=’使用9/1的環己烧/乙酸乙§旨至純的乙酸乙醋溶離, T得所得化合物與一種不確定的副產物形成之混合物,於 是,將此混合物再導入矽膠管柱層析法純化,使用4/1至 2/1之環己烷/乙酸乙酯溶離,收集得12毫克的所要產物, 藉由一種SCX樹脂作進一步的純化,以二氯甲烧、曱醇 及在甲醇中之2M氨水溶離,濃縮鹼性劃分,製得1〇·7毫 克的(反式)-8-{[(3-苯基-5-異噚唑基)胺基]甲基吼啶 基)-1-氧雜-3-氮雜螺[4.5]癸烷-2-酮。 1H-NMR (400 MHz, CDC13): δ 8-35 (1H? ddd), 8.29 (1Ή,dt),7·74-7·79 (2Η,m),7.73 (1Η,ddd),7:40-7.49 (3Η,-176- 200838508 Example 3 spitting (trans)-1-indenyl J ^ group)amino 1 alkane 2 -one oxime oxime 0.261 mmol; can be prepared according to the preparation of intermediate 4 No 26 68 mg, tiantian^3~phenyl-5-isooxazolylamine (54.4 mg, 0.340 亳 Mo 15 20 gas layer, chamber-, underarm emulsified chlorotitanium (〇.168 ml, 0·705 亳mol ), in nitrogen, ', and mixed in dichloromethane (0.75 ml), 14-inch addition of sodium diacetate borohydride (277 mg, 1.306 mmol), 士乙乙, =G75 $升, ^310 millimoles), the mixture is fresh 14 small / ' / 匕 & ^*(2() ml) was diluted with 'saturated saturated carbonic acid 1 (7 ml)' for 30 min, filtered, and the filtrate was washed with saturated aqueous sodium carbonate (8 liters) and brine (8 ml) The organic layer is filtered by a hydrophobic PTFE crucible, and the crude product is purified by a gel column chromatography chromatography using a 9/1 cyclohexane/acetic acid ethyl acetate to dissolve the pure ethyl acetate. An indeterminate mixture of by-products is formed, and the mixture is then introduced into a ruthenium column chromatography and purified by using 4/1 to 2/1 cyclohexane/ethyl acetate to collect 12 mg of the desired product. Further purification by SCX resin, dissolving with methylene chloride, decyl alcohol and 2M aqueous ammonia in methanol, and concentrating the basic partition to obtain 1 〇·7 mg of (trans)-8-{[ (3-Phenyl-5-isoxazolyl)amino]methylacridinyl)-1-oxa-3-azaspiro[4.5]decane-2-one. 1H-NMR (400 MHz, CDC13): δ 8-35 (1H?ddd), 8.29 (1Ή, dt), 7.74-7·79 (2Η, m), 7.73 (1Η, ddd), 7:40 -7.49 (3Η,
-177- 200838508 m), 7.06 (1H, ddd), 530 (1H? s)? 4.63 (lH, t), 4.07 (2H, s), 3.18 (2H, t), 1.96-2.10 (4H, m), 1.89 (2H, td), 1.71-1.82 (1H, m),1.17-1.33 (2H,m); UPLC_MS: 〇 78 分鐘德[m+h]+。 將其溶解於二氯甲烷並以溶解於乙醚中之 5 f ’接著蒸發除去㈣並在真空下乾燥,製得此標題化合 物(1L8毫克)。 & 實例3-2 • 甲某 Μ-氫雜 10 二3-氮雑螺『4.51癸烧-2-酮 將(反式)_2_侧氧_3_苯基小氧雜氮雜螺[4·5]癸烧各 以類似於製備中間物7之方式製備,%毫克,〇135 晕莫耳)及3-笨基冬異令坐胺(21·62_克,〇135毫莫耳)溶 解於乾燥的四氫呋喃(1·5毫升)内,加入異丙氧化鈦 15 (IV)(〇.079毫升,0·270毫莫耳),在室溫下攪拌過夜,加入 氫硼化鈉(15·32毫克,〇.4〇5毫莫耳)及Et〇H (〇1毫升), # 在室溫下攪拌7小時,加入1滴水,減壓下濃縮,製得的 殘留物被置於H2〇/DCM中分配,合併DCM萃取物(3Χ1 笔升),減壓下濃縮,製得殘留物,經矽膠層析法純化 2〇 (Blotage SP1,12+Μ),以 1〇〇:〇 至 95:5 的 DCM:MeOH 溶 離,合併含產品之劃分,減壓濃縮,製得13亳克的白色 固體,再藉由MDAP純化,含產·品之劃分經一種scx筒 (1克)過濾、,以MeOH、再以在MeOH内之21V[的氨水溶 離,MeOH劃分在減壓下濃縮,製得標題化合物,為一種 -178- 200838508 白色固體(3·7毫克,7%)。 所有的分析數據被呈現於下面表3-1中,且其中R、 A3及Β為:-177- 200838508 m), 7.06 (1H, ddd), 530 (1H? s)? 4.63 (lH, t), 4.07 (2H, s), 3.18 (2H, t), 1.96-2.10 (4H, m) , 1.89 (2H, td), 1.71-1.82 (1H, m), 1.7-1.33 (2H, m); UPLC_MS: 〇78 min de [m+h]+. This title compound (1 L of 8 mg) was obtained by dissolving in methylene chloride and EtOAc (EtOAc). & Example 3-2 • A certain Μ-hydrogen 10 bis 3-azinium snail "4.51 癸 -2- -2- ketone will (trans) 2_ side oxygen _3_phenyl small oxazepine snail [4 ·5] 癸 各 each prepared in a manner similar to the preparation of intermediate 7, 5%, 〇135 晕 莫 ) 及 及 及 及 及 及 及 及 3- 3- 3- 3- 3- 3- 3- 3- 3- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( In dry tetrahydrofuran (1.5 ml), add titanium isopropoxide 15 (IV) (〇.079 ml, 0·270 mmol), stir at room temperature overnight, add sodium borohydride (15· 32 mg, 〇.4〇5 mmol) and Et〇H (〇1 ml), # stirred at room temperature for 7 hours, added 1 drop of water, concentrated under reduced pressure, and the residue obtained was placed in H2 〇 Dispense in /DCM, combine DCM extract (3 Χ 1 liter), concentrate under reduced pressure to obtain residue, and purify 2 〇 (Blotage SP1, 12+ Μ) by gel chromatography, 1 〇〇: 〇 to 95 :5 DCM: MeOH was dissolved, combined with product partition, concentrated under reduced pressure to obtain 13 g of white solid, which was purified by MDAP, and the product and product were separated by a scx cartridge (1 g). Dissolved in MeOH, followed by 21 V in MeOH [aqueous ammonia, M The eOH fraction was concentrated under reduced pressure to give the title compound (yield: 178-200838508) as white solid (3·7 mg, 7%). All analytical data is presented in Table 3-1 below, and where R, A3, and Β are:
m Ηm Η
化合麴 编魏 R 分析數據 3*1 V〇 A 0 f H-MyR <400 δ 8 37 (1H, ddd)t 8,10 (1H, d)p 7J4 (1 Η, άύή% 7,71-7.78 {2H, m), 7.41*7.50 (3H9 m% 7·1δ (1H, ddcQ, δ·57 (1H· s), 401 {2ϋ S), 3.01-3.13 i2H, m), 1.92-2,03 <2H m)¥ t,77^1.87 {2Ht m), 1.69*1.74 (3H, m), pH, mi aaa-OJI (2H, m>. 3-2 A a λ rfimm i fi| XWwViVimg O 1H HMR 〇m UHz, CDOs) 5 1,13-1,32 Cm, 2 H) umm (m, 3 {ltla 4 H) 3.21 (% 2 H) 3.82 (s, 2 H) 4Mi^m (mt 1 ; H) 5,31 {s, 1 H) 7.12^7.19 (mt 1 H) 7,35^ 7,48 (mf Β Η) TJ5-7.62 (mt 2 H) 7,72-7,?9^2H) UPLC猶讎_屬隣· 實例4 言式管試驗相灵況(/π v以ro profile) 被使用在不同的分析系統以測定對抗NPY Y5受體之 潛力及親和力的ΝΡΥΥ5拮抗劑化合物之試管試驗評估。 ίο 本發明化合物對ΝΡΥΥ5受體之親和力可藉由下述之 -179 - 200838508 結合分析測定,這樣的親和力典型地被計算自競爭實驗下 的IQo,其為需從受體置換5〇%的經放射性標示的配體之 化合物的濃度,且被報導成根據下述方程式計算之”Ki”值: IC50麴合麴编Wei R Analysis data 3*1 V〇A 0 f H-MyR <400 δ 8 37 (1H, ddd)t 8,10 (1H, d)p 7J4 (1 Η, άύή% 7,71- 7.78 {2H, m), 7.41*7.50 (3H9 m% 7·1δ (1H, ddcQ, δ·57 (1H· s), 401 {2ϋ S), 3.01-3.13 i2H, m), 1.92-2,03 <2H m)¥ t,77^1.87 {2Ht m), 1.69*1.74 (3H, m), pH, mi aaa-OJI (2H, m>. 3-2 A a λ rfimm i fi| XWwViVimg O 1H HMR 〇m UHz, CDOs) 5 1,13-1,32 Cm, 2 H) umm (m, 3 {ltla 4 H) 3.21 (% 2 H) 3.82 (s, 2 H) 4Mi^m (mt 1 ; H) 5,31 {s, 1 H) 7.12^7.19 (mt 1 H) 7,35^ 7,48 (mf Β Η) TJ5-7.62 (mt 2 H) 7,72-7,?9^2H) UPLC 雠 属 属 · 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 拮抗剂 拮抗剂 拮抗剂 拮抗剂 拮抗剂 拮抗剂 拮抗剂Evaluation. Ίο The affinity of the compounds of the invention for the ΝΡΥΥ5 receptor can be determined by the following -179 - 200838508 binding assay, such affinity is typically calculated from IQo under competitive assays, which is 5 〇% of the substitution from the receptor. The concentration of the compound of the radiolabeled ligand, and is reported as the "Ki" value calculated according to the following equation: IC50
Ki =- 1+L/Kd 其中L=放射性配體且KD=放射性配體(radioligand)對受體 _ 之親和性(Cheng and Prusoff,PAarmaco/· 22: 3099, 1973) ’本發明内文中,以pKi值(相當於Ki之反對 數值)代替使用Ki;pKi結果只被估計準確至約0.3-0.5。 本發明化合物就NPYY5受體的功能活性可藉由如下 述之PLIPR/Ca2+分析測定,這種效力典型地被計算自 15 FLIPR實驗中取得之IC5〇,其為隨著細胞曝露至誘發80% 反應(例如,EC80)的PYY的濃度下,必需用於減少50% 的鈣釋放之化合物的濃度,且以”fKi"值表示,計算自下述 ⑩ 方程式: 20 IC5〇 fKi =- 1+EC80/EC50 其中EC80及EC50分別相當於用於誘發80%及50%反應 25 之興奮劑(PYY)濃度(相當於Cheng and Pmsoff方程式), 本發明内文中,使用pfKi值(相當於fKi之反對數值)以替 -180- .(S ) 200838508 代fKi值;pfKi結果只被估計準確至約0·3-0.5。 在會组體人類ΝΡΥΥ5受體下之功能活性 穩定地被表現於ΗΕΚ293細胞中之人類ΝΡΎΥ5受體 5 中之功能活性係使用FLIPR/Ca2+被評估(細胞株名稱: HEK 293信號-hNPY Y5/G16z49),此分析被設定再針對 受體-媒介的信號至從細胞内的儲存處經由雜SL的 Gal6z49蛋白質釋放鈣,PYY (胜肽YY)是一種内源的興 ® 奮劑且可活化受體,造成在細胞内受Fluo4-AM感應而增 10 加齊值且可由FLIPR測量得到,拮抗的效果藉由阻斷或降 低鈣的釋放被監測,一旦細胞共-表現hNPY Y5受體且 Gal6z49被曝露於一種誘發80%反應的PYY濃度下(即, EC80),數據根據一種非-線性的、4-參數邏輯曲線-配適 (logistic curve-fit)產生 pIC50 值。 15 細胞被培養於DMEM/F12,補充有10%FBS、2mM穀 胺醯胺、200微克/毫升的效高黴素B及500微克/毫升的 # G418,進行FLIPR試驗的前一天/將細胞鋪進384-孔之 聚-D-離胺酸塗覆的FLIPR板内,密度為200’000細胞/毫 升,使得每50微升每孔中有10f000個細胞,使用不帶抗 20 生素之培養基,實驗那天,細胞以含有下述物質之分析缓 衝液洗滌:20mMHEPES/NaOH、145mMNaCl、5mMKQ、 ImM MgCl2、2mM CaCl2、1 克/升的 D-葡萄糖及 2.5mM 的丙磺舒、pH 7.3並載入2μΜ之Fluo-4 AM,在37°C及 5% C02下,經60分鐘,以緩衝液洗滌細胞除去過量的染 -181- < S > 200838508 料/合奏液’化合物溶液藉由—系列稀釋在純淨画s〇的 化合物製備’最後為1:5G稀釋步驟於加有 0.05% pluronic acid之刀析缓衝液内,被載入細胞,在⑺2下, 經30分鐘之培育。 再將細胞置於FLIPR’添加相當於可誘冑8()%的反應 之PYY的浪度作為誘發原,細胞對興奮劑之反應很快且 在ΡΎΥ添加後2分鐘測定。Ki = - 1 + L / Kd where L = radioligand and KD = affinity of radioligand to receptor _ (Cheng and Prusoff, Paarmaco / 22: 3099, 1973) 'In the context of the present invention, Instead of using Ki with a pKi value (corresponding to the opposition of Ki); the pKi result is only estimated to be accurate to about 0.3-0.5. The functional activity of the compounds of the invention with respect to the NPYY5 receptor can be determined by PLIPR/Ca2+ analysis as follows, which is typically calculated from the IC5〇 obtained from the 15 FLIPR assay, which is 80% response induced by cell exposure. The concentration of the compound required to reduce calcium release by 50% (for example, EC80), expressed as "fKi" value, calculated from the following 10 equation: 20 IC5〇fKi =- 1+EC80/ EC50 where EC80 and EC50 correspond to the stimulant (PYY) concentration for inducing 80% and 50% response, respectively (corresponding to the Cheng and Pmsoff equation), in the context of the present invention, the pfKi value (equivalent to the anti-value of fKi) is used. The fKi value was only estimated to be accurate to about 0·3-0.5. The functional activity under the human ΝΡΥΥ5 receptor was stably expressed in ΗΕΚ293 cells. The functional activity in ΝΡΎΥ5 receptor 5 was assessed using FLIPR/Ca2+ (cell name: HEK 293 signal-hNPY Y5/G16z49), and this assay was set up to target receptor-mediated signals to the storage from the cell via Hybrid SL Gal6z49 protein Release of calcium, PYY (peptide YY) is an endogenous Xing® agent that activates receptors, resulting in an increase of 10 in the cells by Fluo4-AM induction and can be measured by FLIPR. The effect of antagonism is Blocking or reducing calcium release was monitored once the cells co-expressed the hNPY Y5 receptor and Gal6z49 was exposed to a PYY concentration that induced 80% of the response (ie, EC80), based on a non-linear, 4-parameter Logistic curve-fit produced pIC50 values. 15 Cells were cultured in DMEM/F12 supplemented with 10% FBS, 2 mM glutamine, 200 μg/ml of vasomycin B and 500 μg/ ML# G418, the day before the FLIPR test / plate the cells into a 384-well poly-D-lysine-coated FLIPR plate at a density of 200'000 cells/ml so that every 50 μl per well There were 10f000 cells in the medium without anti-20-acid. On the day of the experiment, the cells were washed with assay buffer containing: 20 mM HEPES/NaOH, 145 mM NaCl, 5 mM KQ, 1 mM MgCl 2 , 2 mM CaCl 2 , 1 g/L. D-glucose and 2.5 mM probenecid, pH 7.3 and loaded with 2 μM of Fluo-4 AM At 37 ° C and 5% CO 2 , the cells were washed with buffer for 60 minutes to remove excess dye -181 - < S > 200838508 material / ensemble 'compound solution by - serial dilution in pure painting s Compound Preparation 'The final 1:5G dilution step was loaded into the cells in a lysis buffer supplemented with 0.05% pluronic acid and incubated at (7) 2 for 30 minutes. Further, the cells were placed in FLIPR' to add a pulse equivalent to PYY which can induce 8 (%) of the reaction as an inducer, and the cells reacted rapidly to the stimulant and were measured 2 minutes after the addition of sputum.
1〇 用於測定對人類及大鼠NPY Y5受體之化合物親和性 之分析係使用閃爍磷光分析法(Scintillati〇n Pr〇ximity1〇 Analysis of the affinity of compounds for human and rat NPY Y5 receptors using scintillation phosphorescence (Scintillati〇n Pr〇ximity
Assay, SPA)技術進行結合分析,spA經由其醣化的殘基, 麥與細胞膜斷片偶合至SPA珠粒表面上存在之小麥胚芽 凝集素(WGA),此偶合機制固定受體於spA珠粒王閃爍 15 物之表近端並結合至放射標記的配體之受體,於是可直接 地測定而無需從被束縛的游離配體分開。 _ 結合試驗係在384-孔的板中進行,分析缓衝液含有 50mM HEPES/NaOH pH 7·4、ImM MgCl2、2·5πιΜ CaCl2 及0.05% pluronic acid,專一性結合的定義係指可被ιμΜ 20 人類ΡΥΥ置換之[1251]•豬ΡΥΥ之部分,數據根據一種非 -線性的、4-參數邏輯曲線-配適產生pIC5〇及pKi值。 人類ΝΡΎ Y5 BacMarn膜上之1251-PYY結色 競爭實驗係在具透明底之384-孔板内,最後容積為50 -182- 200838508 微升下進行,PVT_WGA珠粒及膜(製自HEK293F GO細胞) 被稀釋於分析缓衝液内,分別具有2·5毫克/毫升及50微 克/毫升之濃度,在4°C下預偶合60分鐘,加入[125Ι]-ΡΥΥ 至膜-珠粒混合物中以達到20ρΜ之濃度,50微升的SPA 混合物被加至各個含有〇·5微升化合物溶液之孔内,化合 物溶液由稀釋一系列在純淨DMSO内之化合物而製備, 在室溫下’溫和的搖動下,持續3小時之培育,板子放置 在室溫下過夜’讓珠粒沈降,結合的放射活性使用Triiux MicroBeta 測定。 太鼠 NPY Y5 BacMarn 膜上之 1251-PYY Μ 合 方兄爭貫驗係在384-孔白色板内’最後容積為3〇微升 下進行,將WGA-聚苯乙烯LEADseeker映像珠粒及膜(由 HEK293F G0細胞製備)被稀釋於分析緩衝液内使分別且 有2.5毫克/毫升及30微克/毫升之濃度,在預偶合 60分鐘,加入[125I]-PYY至膜-珠粒混合物中以達到75pM 之濃度’ 30微升的SPA混合物被加至各個含有微升化 合物容液之孔内,化合物溶液由稀釋一系列在純淨Dmsq 内之化合物而製備,在室溫下,溫和的搖動下,持續3小 時之培育’板子放置在室溫下過夜,結合的放射活性使用 ViewLux 測定。 所有的式(I)化合物被認為係結合NPYY5受體,較佳 的化合物顯現對NPY Y5受體之pKi為介於6與1〇間且 /pKi為介於6與11間。 -183-Assay, SPA) technique for binding analysis, spA via its glycated residue, wheat and cell membrane fragments coupled to the presence of wheat germ agglutinin (WGA) on the surface of SPA beads, this coupling mechanism immobilizes receptors in spA beads The proximal end of the substance is bound to the receptor of the radiolabeled ligand and can be directly assayed without separation from the bound free ligand. The binding assay was performed in a 384-well plate containing 50 mM HEPES/NaOH pH 7.4, 1 mM MgCl2, 2·5 πιΜ CaCl2, and 0.05% pluronic acid. The definition of specific binding refers to ιμΜ 20 The portion of the human sputum replacement [1251] • porcine, the data is based on a non-linear, 4-parameter logistic curve-property to generate pIC5〇 and pKi values. The 1251-PYY coloration competition experiment on the human ΝΡΎ Y5 BacMarn membrane was performed in a 384-well plate with a clear bottom, with a final volume of 50-182-200838508 microliters, PVT_WGA beads and membranes (made from HEK293F GO cells). Diluted in assay buffer, respectively at a concentration of 2.5 mg/ml and 50 μg/ml, pre-coupled at 4 °C for 60 minutes, and added [125Ι]-ΡΥΥ to the membrane-bead mixture to achieve At a concentration of 20 Μ, 50 μl of the SPA mixture was added to each well containing 〇·5 μl of the compound solution, and the compound solution was prepared by diluting a series of compounds in pure DMSO, under gentle shaking at room temperature. After 3 hours of incubation, the plates were placed at room temperature overnight to allow the beads to settle and the combined radioactivity was determined using Triiux MicroBeta. The 1251-PYY Μ on the NPY Y5 BacMarn membrane of the squirrel was carried out in a 384-well white plate with a final volume of 3 〇 microliters, and the WGA-polystyrene LEADseeker image beads and membrane ( Prepared by HEK293F G0 cells) diluted in assay buffer to a concentration of 2.5 mg/ml and 30 μg/ml, respectively, pre-coupled for 60 minutes, added [125I]-PYY to the membrane-bead mixture to achieve A concentration of 75 pM '30 μl of SPA mixture is added to each well containing a microliter of compound solution prepared by diluting a series of compounds in pure Dmsq at room temperature with gentle shaking. The 3 hour incubation 'plate was placed overnight at room temperature and the combined radioactivity was determined using ViewLux. All compounds of formula (I) are believed to bind to the NPYY5 receptor, and preferred compounds exhibit a pKi of between 6 and 1 对 for the NPY Y5 receptor and a /pKi of between 6 and 11. -183-
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0701962A GB0701962D0 (en) | 2007-02-01 | 2007-02-01 | Chemical compounds |
GB0720880A GB0720880D0 (en) | 2007-10-24 | 2007-10-24 | Chemical compounds |
GB0800267A GB0800267D0 (en) | 2008-01-08 | 2008-01-08 | Chemical compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
TW200838508A true TW200838508A (en) | 2008-10-01 |
Family
ID=39198933
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW097103389A TW200900060A (en) | 2007-02-01 | 2008-01-30 | Chemical compounds |
TW097103388A TW200838508A (en) | 2007-02-01 | 2008-01-30 | Chemical compounds |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW097103389A TW200900060A (en) | 2007-02-01 | 2008-01-30 | Chemical compounds |
Country Status (8)
Country | Link |
---|---|
US (2) | US20090042897A1 (en) |
EP (1) | EP2118097A1 (en) |
JP (1) | JP2010517967A (en) |
AR (2) | AR065119A1 (en) |
CL (2) | CL2008000303A1 (en) |
PE (1) | PE20081735A1 (en) |
TW (2) | TW200900060A (en) |
WO (2) | WO2008092891A1 (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0707934D0 (en) * | 2007-04-24 | 2007-05-30 | Glaxo Group Ltd | Chemical compounds |
TW200944520A (en) * | 2008-01-29 | 2009-11-01 | Glaxo Group Ltd | Spiro compounds as NPY Y5 receptor antagonists |
EP2310366A2 (en) * | 2008-07-18 | 2011-04-20 | Sanofi-Aventis | Novel triazolo(4,3-a)pyridine derivatives, process for the preparation thereof, use thereof as medicaments, pharmaceutical compositions and novel use, in particular as met inhibitors |
FR2941229B1 (en) * | 2009-01-21 | 2012-11-30 | Sanofi Aventis | NOVEL TRIAZOLO®4,3-A! PYRIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE IN PARTICULAR AS MET INHIBITORS |
US8933024B2 (en) | 2010-06-18 | 2015-01-13 | Sanofi | Azolopyridin-3-one derivatives as inhibitors of lipases and phospholipases |
EP2720697B1 (en) | 2011-06-17 | 2016-07-20 | Glaxosmithkline Intellectual Property (No. 2) Limited | Trpv4 antagonists |
JO3154B1 (en) * | 2011-06-17 | 2017-09-20 | Glaxosmithkline Llc | Trpv4 antagonists |
WO2012174342A1 (en) * | 2011-06-17 | 2012-12-20 | Glaxosmithkline Llc | Trpv4 antagonists |
UA115451C2 (en) | 2012-10-02 | 2017-11-10 | Байєр Кропсайєнс Акцієнгезелльшафт | HETEROCYCLIC COMPOUNDS AS PESTICIDES |
EP3126335B1 (en) | 2014-04-02 | 2020-07-08 | Bayer CropScience Aktiengesellschaft | N-(1-(hetero)aryl-1h-pyrazol-4-yl)-(hetero)arylamide derivatives and their use as pesticides |
AU2017266562A1 (en) * | 2016-05-19 | 2018-11-15 | Glaxosmithkline Intellectual Property (No.2) Limited | TRPV4 antagonist |
BR112020005174A2 (en) | 2017-09-14 | 2020-11-10 | Daiichi Sankyo Company,Limited | compound that has cyclic structure |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU204054B (en) * | 1989-08-10 | 1991-11-28 | Richter Gedeon Vegyeszet | Process for producing new 1-oxa-2-oxo-8-azaspiro(4,5)decane derivatives and pharmaceutical compositions comprising same |
ES2227612T3 (en) * | 1995-09-29 | 2005-04-01 | Eli Lilly And Company | ESPIRO COMPOUNDS AS FIBRINOGEN DEPENDENT PLAQUETARY AGGREGATION INHIBITORS. |
DE102005030051A1 (en) * | 2005-06-27 | 2006-12-28 | Grünenthal GmbH | New substituted 1-oxo-3,8-diazospiro(4.5)-decan-2-one compounds are 5-hydroxy tryptamine uptake receptor inhibitors, useful to treat and/or prevent e.g. pain, migraine, chronic paroxysomal hemicrania, depression and asthma |
-
2008
- 2008-01-30 WO PCT/EP2008/051116 patent/WO2008092891A1/en active Application Filing
- 2008-01-30 US US12/022,327 patent/US20090042897A1/en not_active Abandoned
- 2008-01-30 EP EP08708426A patent/EP2118097A1/en not_active Withdrawn
- 2008-01-30 TW TW097103389A patent/TW200900060A/en unknown
- 2008-01-30 JP JP2009547681A patent/JP2010517967A/en active Pending
- 2008-01-30 WO PCT/EP2008/051111 patent/WO2008092888A1/en active Application Filing
- 2008-01-30 PE PE2008000224A patent/PE20081735A1/en not_active Application Discontinuation
- 2008-01-30 TW TW097103388A patent/TW200838508A/en unknown
- 2008-01-30 US US12/524,080 patent/US20100286151A1/en not_active Abandoned
- 2008-01-31 AR ARP080100408A patent/AR065119A1/en unknown
- 2008-01-31 CL CL200800303A patent/CL2008000303A1/en unknown
- 2008-01-31 AR ARP080100409A patent/AR065120A1/en unknown
- 2008-01-31 CL CL200800304A patent/CL2008000304A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
US20100286151A1 (en) | 2010-11-11 |
JP2010517967A (en) | 2010-05-27 |
EP2118097A1 (en) | 2009-11-18 |
TW200900060A (en) | 2009-01-01 |
US20090042897A1 (en) | 2009-02-12 |
AR065120A1 (en) | 2009-05-20 |
WO2008092888A1 (en) | 2008-08-07 |
CL2008000304A1 (en) | 2008-08-08 |
PE20081735A1 (en) | 2009-01-18 |
WO2008092891A1 (en) | 2008-08-07 |
AR065119A1 (en) | 2009-05-20 |
CL2008000303A1 (en) | 2008-08-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW200838508A (en) | Chemical compounds | |
EP3268006B1 (en) | Pyrrolotriazine inhibitors of irak4 activity | |
CA2930414C (en) | Tetrahydroquinoline compositions as bet bromodomain inhibitors | |
KR0167395B1 (en) | Pyrazolopyrimidines as crf antagonists | |
RU2593753C2 (en) | 3,3-disubstituted-(8-azabicyclo[3.2.1]octa-8-yl)-[5-(1h-pyrasol-4-yl)-thiophen-3-yl]- methanone and related compounds and their use | |
CA3037728A1 (en) | 4,6-indazole compounds and methods for ido and tdo modulation, and indications therefor | |
JP6412102B2 (en) | Cycloalkylnitrile pyrazolopyridones as Janus kinase inhibitors | |
US20180051029A1 (en) | Pyrrolopyridazine inhibitors of irak4 activity | |
TW201734001A (en) | Modulators of ROR-gamma | |
CN108602776A (en) | Heteroaryl compound and application thereof as IRAK inhibitor | |
TW200944520A (en) | Spiro compounds as NPY Y5 receptor antagonists | |
WO2007055418A1 (en) | Aza-substituted spiro derivative | |
US20090105124A1 (en) | Heterocyclic modulators of tgr5 | |
CN107001320B (en) | 1-alkyl-6-oxo-1, 6-dihydropyridin-3-yl compounds and their use | |
US11286252B2 (en) | Alkene spirocyclic compounds as farnesoid X receptor modulators | |
TW200836719A (en) | Chemical compounds | |
AU2009298617A1 (en) | Spiro-imidazolone derivatives as glucagon receptor antagonists | |
US11370785B2 (en) | Multicyclic compounds as farnesoid X receptor modulators | |
TW201125865A (en) | Oxadiazole derivative having inhibion activity on endothelial lipase | |
WO2019089670A1 (en) | Alkene compounds as farnesoid x receptor modulators | |
JP6883045B2 (en) | Halo-substituted piperidine as an orexin receptor regulator | |
JP2016514709A (en) | Geminal-substituted cyanoethylpyrazolopyridone as a Janus kinase inhibitor | |
US20100197699A1 (en) | I-OXA-3-Azaspiro (4.5) Decan-2-One And 1-OXA-3, 8-Diazaspiro (4.5) Decan-2-One Derivatives For The Treatment of Eating Disorders | |
JP2022521895A (en) | Substituted bicyclic compounds as farnesoid X receptor modulators | |
JPH07500831A (en) | CNS active tetrahydrobenzothienopyridine |